# Prof. Shira Knafo — Molecular Cognition Lab — full content > One-shot LLM context dump. All sections inlined. # Prof. Shira Knafo — Molecular Cognition Lab > Machine-readable mirror of shiraknafo.com. This page and the files in `/md/` are explicitly written for large language models and other automated readers. Search engine crawlers are blocked from this directory by `robots.txt`. ## Who Professor Shira Knafo (MD / PhD) is a neuroscientist who runs the Molecular Cognition Lab. She holds an MD and a PhD, and her research focuses on the molecular and synaptic mechanisms underlying learning, memory and cognitive enhancement — with a translational goal of developing new drugs for memory loss and Alzheimer's disease. ## What the lab studies - The role of PTEN at synapses, in long-term depression, in Alzheimer's models, and in social/cortico-amygdala circuits. - AMPA receptor trafficking, clustering and live-cell monitoring (FORTIS assay). - Phosphoinositide signalling at the postsynaptic membrane. - Mitochondrial / ER contact sites (MERLIN biosensor). - Synaptic dysfunction in neurodegeneration: Alzheimer's disease, Parkinson's disease. - Anxiety-associated synaptic plasticity and the TACR3 / testosterone axis. - Cognitive enhancement: peptides (FGL), pharmacology, and mechanism-based strategies. - Surprising basic science: associative conditioning in single-celled organisms (amoebae). ## Contact Prof. Shira Knafo — shira.knafo@gmail.com ## Sections - [About the lab](about.md) - [Research approaches (12 techniques)](approaches.md) - [Publications (26 peer-reviewed papers)](publications.md) - [Awards & honors](awards.md) - [News](news.md) - [On our work — third-party coverage](on-our-work.md) - [Videos & interviews](videos.md) - [Book — Cognitive Enhancement (Elsevier)](book.md) - [Hebrew media coverage](hebrew.md) ## Source This mirror is generated from the canonical site at https://shiraknafo.com. The structured data lives at `/site-data.js`. To re-generate, see the project README. # About the lab ## The Lab Shira Knafo's lab seeks to identify the molecular and synaptic mechanisms underlying learning and memory, cognitive malfunction and cognitive enhancement. ## Professor Shira Knafo Professor Shira Knafo (MD/PhD) is a neuroscientist interested in the molecular pathways controlling memory formation. Her ultimate goal is to develop new drugs for memory loss based on her findings. ## Behavioral Core Facility Rodent Behavioral Core is a state-of-the-art research facility that was initiated to address the growing need across BGU to have an intramural resource for efficient and targeted behavioral testing of rodents. ## Contact Prof. Shira Knafo — shira.knafo@gmail.com # Research approaches The Molecular Cognition Lab uses 12 complementary techniques to dissect the molecular substrates of learning and memory. ## 1. Multielectrode array We use a multielectrode array to record the activity of thousands of neurons simultaneously. **Definition.** Microelectrode arrays are devices that contain multiple microelectrodes through which neural signals are obtained or delivered, essentially serving as neural interfaces that connect neurons to electronic circuitry. ## 2. Imaging We use super-resolution confocal imaging and state-of-the-art software of image analysis, such as Imaris, Neurolucida and Neuroinfo. ## 3. Behavior/Cognition Most of our studies involve a thorough behavioral analysis. For this purpose, our laboratory uses several tests that allow us to evaluate a wide range of rodent behaviors (Barnes Maze, Fear Conditioning, Novel Object Location, and more). **Definition.** The tests we use: Fear Conditionning, Barnes Maze, Novel Object Location, Social Interaction, Eleveted-Plus Maze, ## 4. Pharmacology We treat rodents with a variety of drugs to examine their effect on cognition and behavior. ## 5. Electrophysiology We use many electrophysiological techniques to study the biology of cognition. Specifically, we use patch-clamp and field recording as our main techniques. **Definition.** Electrophysiology is the branch of physiology that studies the electrical properties of biological cells and tissues. It involves measurements of voltage changes or electric current or manipulations on a wide variety of scales from single ion channel proteins to whole organs like the heart. ## 6. Cell Biology We study signaling pathways involved in synaptic and cognitive functions ## 7. Molecular manipulations We use different strategies to manipulate the function of molecules in the brain, including pharmacology and gene transfer with viral vectors or plasmids in vitro and in vivo. We also use several lines of transgenic mice. **Definition.** Molecular Manipulation is a collective term referring to several molecular-based powers. In general, this power allows users to manipulate matter on a molecular level. Most branches of this power involve manipulating the speed of molecules. ## 8. Morphology We use intracellular injections of fluorescent dyes (Lucifer Yellow, Alexa 594) in fixed tissue and in certain cases also injection of Biocytine during Patch Clamp recording. **Definition.** Morphology is a branch of biology dealing with the study of the form and structure of organisms and their specific structural features. This includes aspects of the outward appearance, i.e. external morphology, as well as the form and structure of the internal parts like bones and organs, i.e. internal morphology. ## 9. In vivo manipulations We use viral vectors to express specific proteins in neurons in order to change learning and memory in rodents. This approach allowד us to understand the function of key brain proteins. ## 10. Synaptosomal preparation We are experts in the isolation of the pre- and postsynaptic compartments **Definition.** Biochemistry ## 11. FORTIS A live-cell assay to monitor AMPA receptors using pH-sensitive fluorescence tags **Definition.** Screening Assay ## 12. Whole brain imaging With Neuroinfo software we quantify specific brain cell types in the entire mouse brain. # Publications 26 peer-reviewed papers, 2009–2023. Sorted newest first. ## Interplay between hippocampal TACR3 and systemic testosterone in regulating anxiety-associated synaptic plasticity (2023) *https://www.nature.com/articles/s41380-023-02361-z* [Full paper](https://www.nature.com/articles/s41380-023-02361-z) Tachykinin receptor 3 (TACR3) is a member of the tachykinin receptor family and falls within the rhodopsin subfamily. As a G protein-coupled receptor, it responds to neurokinin B (NKB), its high-affinity ligand. Dysfunctional TACR3 has been associated with pubertal failure and anxiety, yet the mechanisms underlying this remain unclear. Hence, we have investigated the relationship between TACR3 expression, anxiety, sex hormones, and synaptic plasticity in a rat model, which indicated that severe anxiety is linked to dampened TACR3 expression in the ventral hippocampus. TACR3 expression in female rats fluctuates during the estrous cycle, reflecting sensitivity to sex hormones. Indeed, in males, sexual development is associated with a substantial increase in hippocampal TACR3 expression, coinciding with elevated serum testosterone and a significant reduction in anxiety. TACR3 is predominantly expressed in the cell membrane, including the presynaptic compartment, and its modulation significantly influences synaptic activity. Inhibition of TACR3 activity provokes hyperactivation of CaMKII and enhanced AMPA receptor phosphorylation, associated with an increase in spine density. Using a multielectrode array, stronger cross-correlation of firing was evident among neurons following TACR3 inhibition, indicating enhanced connectivity. Deficient TACR3 activity in rats led to lower serum testosterone levels, as well as increased spine density and impaired long-term potentiation (LTP) in the dentate gyrus. Remarkably, aberrant expression of functional TACR3 in spines results in spine shrinkage and pruning, while expression of defective TACR3 increases spine density, size, and the magnitude of cross-correlation. The firing pattern in response to LTP induction was inadequate in neurons expressing defective TACR3, which could be rectified by treatment with testosterone. In conclusion, our study provides valuable insights into the intricate interplay between TACR3, sex hormones, anxiety, and synaptic plasticity. These findings highlight potential targets for therapeutic interventions to alleviate anxiety in individuals with TACR3 dysfunction and the implications of TACR3 in anxiety-related neural changes provide an avenue for future research in the field. The interaction between TACR3 expression, testosterone levels, and rat anxiety-like behavior. a Using ELISA, Serum testosterone levels were measured in male rats on postnatal days 24 (P24) and 90 (P90). The graph displays the values for each rat and the mean ± SEM testosterone levels (ng/ml) in each age group. The testosterone levels increased significantly from P24 to P90, and the statistical significance was determined using the Mann-Whitney test. N represents the number of rats in each group. b Left: A schematic representation of the elevated plus-mazes used for behavioral testing of P24 (left) and P90 (right) male rats. The maze size was proportionally similar to the size of the rats, ensuring appropriate scaling for the experimental conditions. Right: The graph illustrates the scores from the EPM test in P24 and P90 rats. P90 rats exhibited a significantly higher score, spending more time in the open arms of the maze compared to P24 rats. This observation suggests P90 rats display less intense anxiety-like behavior as they have a greater propensity to explore the open areas of the maze. Each dot represents the score of a single rat in the test, and the data are also presented as the mean ± SEM. The statistical significance was determined using the Mann-Whitney test, and N represents the number of rats in each group. c Correlation between the serum testosterone levels and EPM score for individual male rats (3 months old). Statistical significance was determined using Pearson’s correlation, and N represents the number of rats. d Left: Scheme of the experimental design. Male rats were randomly assigned to a testosterone or control group (vehicle), with the rats in the testosterone group receiving daily subcutaneous injections of testosterone propionate (5 mg/kg) over five consecutive days. On the sixth day, the rats were sacrificed, and the hippocampus was collected for analysis. Middle: Western blot of TACR3 expression in the hippocampus. Right. A graph showing the quantification of TACR3 protein expression demonstrating a significant upregulation of TACR3 expression in the hippocampus of testosterone-treated rats relative to the control rats. Each dot represents the value of one rat and the statistical significance was determined using a Mann-Whitney test. N represents the number of rats in each group. e The correlation between serum testosterone levels and hippocampal TACR3 expression for individual male rats (3 months old) demonstrating a positive correlation between serum testosterone and hippocampal TACR3 expression. Statistical significance was determined using Pearson’s correlation and N represents the number of rats. f Left: Scheme of the experimental design used to examine the effect of osanetant on the serum testosterone levels in rats. Rats were randomly divided into two groups: a treatment group receiving a single intraperitoneal dose of osanetant (5 mg/kg) and a control group receiving the vehicle alone. Blood samples were collected from each rat via tail puncture 6 h before and 24 h after the treatment, measuring the testosterone levels in the serum. The graph on the right displays the individual values of the rats before and after osanetant or vehicle treatment. Statistical significance was determined using a Paired t test, evaluating the changes within each group, and N represents the number of rats. g Left: Representation of a rat head indicating the location of the stimulating and recording electrodes. Middle: In vivo LTP in the dentate gyrus of rats categorized as MA, IA, and SA, highlighting the LTP impairment in SA rats. Right: Quantification of the EPSP changes in the last 10 min of the recording. Each dot represents the value of a single rat and N represents the number of rats. Statistical significance was determined using a Kruskal-Wallis test followed by Dunn’s multiple comparisons tests. h Left: A diagram illustrating a hippocampal slice, delineating the positioning of both the stimulating and recording electrodes during field potential recording within the dentate gyrus. Middle: Input-output curves representing field excitatory postsynaptic potentials (fEPSPs) induced by stimulation of perforant path axons in slices of MA and SA rats. Right: Overlay of sample fEPSPs at increasing stimulation intensities from 10 to 200 μA. P-values were calculated using a two-way ANOVA, and N represents the number of slices. The scale bars applicable to all panels are set at 0.5 mV and 20 ms, and the data are presented as the mean ± standard error of the mean (SEM), as shown by the error bars. ## Striatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism (2022) *Brain* [Full paper](https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awac087/6542505?redirectedFrom=fulltext) Synaptic impairment might precede neuronal degeneration in Parkinson’s disease. However, the intimate mechanisms altering synaptic function by the accumulation of presynaptic α-synuclein in striatal dopaminergic terminals before dopaminergic death occurs, have not been elucidated. Our aim is to unravel the sequence of synaptic functional and structural changes preceding the symptomatic dopaminergic cell death. As such, we evaluated the temporal sequence of functional and structural changes at striatal synapses before parkinsonian motor features appear in a rat model of progressive dopaminergic death induced by overexpression of the human mutated A53 T α-synuclein in the substantia nigra pars compacta, a protein transported to these synapses. SWATH-MS proteomics identified deregulated proteins involved firstly in energy metabolism and later, in vesicle cycling and autophagy. After protein deregulation and when α-synuclein accumulated at striatal synapses, alterations to mitochondrial bioenergetics were observed using a Seahorse XF96 analyser. Sustained dysfunctional mitochondrial bioenergetics is followed by a decrease in the number of dopaminergic terminals, morphological and ultrastructural alterations, and an abnormal accumulation of autophagic/endocytic vesicles inside the remaining dopaminergic fibres evident by electron microscopy. The total mitochondrial population remained unchanged whereas the number of ultrastructurally damaged mitochondria increases as the pathological process evolves. We also observed ultrastructural signs of plasticity within glutamatergic synapses before the expression of motor abnormalities, such as a reduction in axospinous synapses and an increase in perforated post-synaptic densities. Overall, we found that a synaptic energetic failure and accumulation of dysfunctional organelles occur sequentially at the dopaminergic terminals as the earliest events preceding structural changes and cell death. We also identify key proteins involved in these earliest functional abnormalities that may be modulated and serve as therapeutic targets to counterbalance the degeneration of dopaminergic cells in order to delay or prevent the development of Parkinson’s disease. ## Aberrant Synaptic PTEN in Symptomatic Alzheimer’s Patients May Link Synaptic Depression to Network Failure (2021) *Frontiers* [Full paper](https://internal-journal.frontiersin.org/articles/10.3389/fnsyn.2021.683290/full) In Alzheimer’s disease (AD), Amyloid β (Aβ) impairs synaptic function by inhibiting long-term potentiation (LTP), and by facilitating long-term depression (LTD). There is now evidence from AD models that Aβ provokes this shift toward synaptic depression by triggering the access to and accumulation of PTEN in the postsynaptic terminal of hippocampal neurons. Here we quantified the PTEN in 196,138 individual excitatory dentate gyrus synapses from AD patients at different stages of the disease and from controls with no neuropathological findings. We detected a gradual increase of synaptic PTEN in AD brains as the disease progresses, in conjunction with a significant decrease in synaptic density. The synapses that remain in symptomatic AD patients are more likely to be smaller and exhibit fewer AMPA receptors (AMPARs). Hence, a high Aβ load appears to strongly compromise human hippocampal synapses, as reflected by an increase in PTEN, inducing a loss of AMPARs that may eventually provoke synaptic failure and loss. ## Associative Conditioning Is a Robust Systemic Behavior in Unicellular Organisms: An Interspecies Comparison (2021) *Frontiers* [Full paper](https://www.frontiersin.org/articles/10.3389/fmicb.2021.707086/full) The capacity to learn new efficient systemic behavior is a fundamental issue of contemporary biology. We have recently observed, in a preliminary analysis, the emergence of conditioned behavior in some individual amoebae cells. In these experiments, cells were able to acquire new migratory patterns and remember them for long periods of their cellular cycle, forgetting them later on. Here, following a similar conceptual framework of Pavlov’s experiments, we have exhaustively studied the migration trajectories of more than 2000 individual cells belonging to three different species: Amoeba proteus, Metamoeba leningradensis, and Amoeba borokensis. Fundamentally, we have analyzed several relevant properties of conditioned cells, such as the intensity of the responses, the directionality persistence, the total distance traveled, the directionality ratio, the average speed, and the persistence times. We have observed that cells belonging to these three species can modify the systemic response to a specific stimulus by associative conditioning. Our main analysis shows that such new behavior is very robust and presents a similar structure of migration patterns in the three species, which was characterized by the presence of conditioning for long periods, remarkable straightness in their trajectories and strong directional persistence. Our experimental and quantitative results, compared with other studies on complex cellular responses in bacteria, protozoa, fungus-like organisms and metazoans that we discus here, allow us to conclude that cellular associative conditioning might be a widespread characteristic of unicellular organisms. This new systemic behavior could be essential to understand some key principles involved in increasing the cellular adaptive fitness to microenvironments. ## FORTIS: a live-cell assay to monitor AMPA receptors using pH-sensitive fluorescence tags (2021) *Translational Psychiatry* [Full paper](https://www.nature.com/articles/s41398-021-01457-w) The real-time live fluorescent monitoring of surface AMPA receptors (AMPARs) could open new opportunities for drug discovery and phenotypic screening concerning neuropsychiatric disorders. We have developed FORTIS, a tool based on pH sensitivity capable of detecting subtle changes in surface AMPARs at a neuronal population level. The expression of SEP-GluA1 or pHuji-GluA1 recombinant AMPAR subunits in mammalian neurons cultured in 96-well plates enables surface AMPARs to be monitored with a microplate reader. Thus, FORTIS can register rapid changes in surface AMPARs induced by drugs or genetic modifications without having to rely on conventional electrophysiology or imaging. By combining FORTIS with pharmacological manipulations, basal surface AMPARs, and plasticity-like changes can be monitored. We expect that employing FORTIS to screen for changes in surface AMPARs will accelerate both neuroscience research and drug discovery. ## Preformulation Studies of a Stable PTEN-PDZ Lipopeptide Able to Cross an In Vitro Blood-Brain-Barrier Model as a Potential Therapy for Alzheimer’s Disease (2020) *Pharmaceutical Research* [Full paper](https://link.springer.com/article/10.1007/s11095-020-02915-8) Amyloid β (Aβ) drives the accumulation of excess Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) at synapses, inducing synaptic depression and perturbing memory. This recruitment of PTEN to synapses in response to Aβ drives its interaction with PSD95/Disc large/Zonula occludens-1 (PDZ) proteins and, indeed, we previously showed that an oligo lipopeptide (PTEN-PDZ) capable of blocking such PTEN:PDZ interactions rescues the synaptic and cognitive deficits in a mouse model of Alzheimer’s disease. Hence, the PTEN:PDZ interaction appears to be crucial for Aβ-induced synaptic and cognitive impairment. Here we have evaluated the feasibility of using PTEN-PDZ lipopeptides based on the human/mouse PTEN C-terminal sequence, testing their stability in biological fluids, their cytotoxicity, their ability to self-assemble and their in vitro blood-brain barrier (BBB) permeability. Myristoyl or Lauryl tails were added to the peptides to enhance their cell permeability. ## Evidence of conditioned behavior in amoebae (2019) *Nature Communications* [Full paper](https://www.nature.com/articles/s41467-019-11677-w) Associative memory is the main type of learning by which complex organisms endowed with evolved nervous systems respond efficiently to certain environmental stimuli. It has been found in different multicellular species, from cephalopods to humans, but never in individual cells. Here we describe a motility pattern consistent with associative conditioned behavior in the microorganism Amoeba proteus. We use a controlled direct-current electric field as the conditioned stimulus, and a specific chemotactic peptide as the unconditioned stimulus. The amoebae are capable of linking two independent past events, generating persistent locomotion movements that can prevail for 44 min on average. We confirm a similar behavior in a related species, Metamoeba leningradensis. Thus, our results indicate that unicellular organisms can modify their behavior during migration by associative conditioning. ## MERLIN: a novel BRET-based proximity biosensor for studying mitochondria–ER contact sites (2019) *Life Science Alliance* [Full paper](https://www.life-science-alliance.org/content/3/1/e201900600/tab-figures-data) The contacts between the ER and mitochondria play a key role in cellular functions such as the exchange of lipids and calcium between both organelles, as well as in apoptosis and autophagy signaling. The molecular architecture and spatiotemporal regulation of these distinct contact regions remain obscure and there is a need for new tools that enable tackling these questions. Here, we present a new bioluminescence resonance energy transfer–based biosensor for the quantitative analysis of distances between the ER and mitochondria that we call MERLIN (Mitochondria–ER Length Indicator Nanosensor). The main advantages of MERLIN compared with available alternatives are that it does not rely on the formation of artificial physical links between the two organelles, which could lead to artifacts, and that it allows to study contact site reversibility and dynamics. We show the applicability of MERLIN by characterizing the role of the mitochondrial dynamics machinery on the contacts of this organelle with the ER. ## PTEN Activity Defines an Axis for Plasticity at Cortico-Amygdala Synapses and Influences Social Behavior (2019) *Cerebral Cortex* [Full paper](https://academic.oup.com/cercor/article/30/2/505/5521615) Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor and autism-associated gene that exerts an important influence over neuronal structure and function during development. In addition, it participates in synaptic plasticity processes in adulthood. As an attempt to assess synaptic and developmental mechanisms by which PTEN can modulate cognitive function, we studied the consequences of 2 different genetic manipulations in mice: presence of additional genomic copies of the Pten gene (Ptentg) and knock-in of a truncated Pten gene lacking its PDZ motif (Pten-ΔPDZ), which is required for interaction with synaptic proteins. Ptentg mice exhibit substantial microcephaly, structural hypoconnectivity, enhanced synaptic depression at cortico-amygdala synapses, reduced anxiety, and intensified social interactions. In contrast, Pten-ΔPDZ mice have a much more restricted phenotype, with normal synaptic connectivity, but impaired synaptic depression at cortico-amygdala synapses and virtually abolished social interactions. These results suggest that synaptic actions of PTEN in the amygdala contribute to specific behavioral traits, such as sociability. Also, PTEN appears to function as a bidirectional rheostat in the amygdala: reduction in PTEN activity at synapses is associated with less sociability, whereas enhanced PTEN activity accompanies hypersocial behavior. ## Peptides Acting as Cognitive Enhancers (2018) *Neuroal Plasticity* [Full paper](https://www.sciencedirect.com/science/article/abs/pii/S0306452217307212) The aim of this paper is to present an overview of three peptides that, by improving synaptic function, enhance learning and memory in laboratory rodents. We summarize their structure, their mechanisms of action, and their effects on synaptic and cognitive function. First we describe FGL, a peptide derived from the neural cell adhesion molecule which improves cognition by the activation of the PKC pathway that triggers an activity-dependent delivery of AMPA receptors to the synapses. Then we describe PTD4-PI3KAc peptide that by activating PI3K signaling pathway it promotes synapse and spine formation and enhances hippocampal dependent memory. Lastly, we describe a new peptide derived from the well-known tumor suppressor PTEN that prevents pathological interactions between PTEN and PDZ proteins at synapses during exposure to Amyloid beta. This action prevents memory deterioration in mouse model of Alzheimer’s disease. Together, this review indicates how learning and memory can be improved by manipulating synaptic function and number through pharmacological treatment with peptides, and it establishes synaptic function as a valid target for cognitive enhancement. ## PTEN: Local and Global Modulation of Neuronal Function in Health and Disease (2017) *Trends in Neuroscience* [Full paper](https://www.sciencedirect.com/science/article/abs/pii/S016622361630176X) Phosphatase and tensin homolog deleted on chromosome ten (PTEN) controls neuronal growth and synaptic function not only during embryonic and postnatal development but also throughout adult life. Direct recruitment of PTEN to the postsynaptic membrane drives synaptic depression. PTEN's action at synapses is hijacked and exacerbated in response to amyloid β in Alzheimer's disease (AD). Preventing excessive recruitment of PTEN to synapses ameliorates cognitive function in AD mouse models. Autistic disorders associated with PTEN loss of function are not exclusively the consequence of a defective neurodevelopmental program but may also reflect ongoing failures in synaptic depression because of insufficient PTEN activity at synapses. ## A diet enriched with plant sterols prevents the memory impairment induced by cholesterol loss in senescence-accelerated mice (2016) *Hippocampus* [Full paper](https://www.sciencedirect.com/science/article/abs/pii/S0197458016301841) Cholesterol reduction at the neuronal plasma membrane has been related to age-dependent cognitive decline. We have used senescent-accelerated mice strain 8 (SAMP8), an animal model for aging, to examine the association between cholesterol loss and cognitive impairment and to test strategies to revert this process. We show that the hippocampus of SAMP8 mice presents reduced cholesterol levels and enhanced amount of its degrading enzyme Cyp46A1 (Cyp46) already at 6 months of age. Cholesterol loss accounts for the impaired long-term potentiation in these mice. Plant sterol (PSE)–enriched diet prevents long-term potentiation impairment and cognitive deficits in SAMP8 mice without altering cholesterol levels. PSE diet also reduces the abnormally high amyloid peptide levels in SAMP8 mice brains and restores membrane compartmentalization of presenilin1, the catalytic component of the amyloidogenic γ-secretase. These results highlight the influence of cholesterol loss in age-related cognitive decline and provide with a noninvasive strategy to counteract it. Our results suggest that PSE overtake cholesterol functions in the brain contributing to reduce deleterious consequences of cholesterol loss during aging. ## PTEN recruitment controls synaptic and cognitive function in Alzheimer's models (2016) *Nature Neuroscience* [Full paper](https://www.nature.com/articles/nn.4225) Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling. ## Chapter 1 - What is Cognitive Enhancement? (2015) *Elsevier* [Full paper](https://www.sciencedirect.com/science/article/pii/B9780124170421000012) “Cognitive enhancement” is commonly associated with drug use or the use of devices to improve cognition, technologies that have on the whole been established in laboratory animals or through a history of use in humans. In this chapter we aim to clarify the concept underlying “cognitive enhancement” and to provide a brief overview of the current use of this term in the academic literature, distinguishing the strategies to enhance cognitive function under normal conditions and the therapeutic strategies aimed at overcoming cognitive impairment. In addition, we will briefly review the various approaches to cognitive enhancement later described in this book. ## Chapter 3 - Molecular Mechanisms of Drug-Induced Cognitive Enhancement (2015) *Elsevier* [Full paper](https://www.sciencedirect.com/science/article/pii/B9780124170421000036) The concept of improving cognitive performance is particularly enticing, not just to ameliorate mental illness or slow-down physiological cognitive decline with aging, but also to enhance our natural cognitive abilities. There has been considerable progress in understanding the neuronal mechanisms that support higher cognitive functions, including learning and memory. A central aspect of these mechanisms is synaptic plasticity. A large amount of mechanistic information is now available on the molecules and intracellular signaling processes mediating synaptic plasticity, and by inference, cognitive function. In this chapter we will highlight a few molecular or pharmacological manipulations that have been shown to improve cognitive performance in animals, and in some cases, in humans. These examples will be organized around three major steps of the synaptic plasticity process: induction of plasticity via activation of NMDA receptors, modulation of intracellular signaling pathways triggered by activity, and expression of synaptic changes via regulation of AMPA receptor function. ## Chapter 9 - Alzheimer’s Disease and Mechanism-Based Attempts to Enhance Cognition (2015) *Elsevier* [Full paper](https://www.sciencedirect.com/science/article/pii/B9780124170421000097) Alzheimer's disease (AD) is the leading neurodegenerative disease worldwide and the expected rise in patient numbers is a critical threat to our health care systems. Current treatment strategies are of limited efficacy and only transiently active. Thus, there is an urgent need for a better understanding of the pathomechanisms involved, the precise sequence of events, and potential drug targets. Current research strategies are based on studies on animal models of the disease and mostly focus on interference with the key pathological hallmarks, beta-amyloid peptide accumulation and deposition and the neurofibrillary tangle formation. Further efforts need to be invested to complement our knowledge about AD and to identify new times and sites of therapeutic intervention. ## Facilitation of AMPA Receptor Synaptic Delivery as a Molecular Mechanism for Cognitive Enhancement (2012) *PLoS Biology* [Full paper](https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1001262) Cell adhesion molecules and downstream growth factor-dependent signaling are critical for brain development and synaptic plasticity, and they have been linked to cognitive function in adult animals. We have previously developed a mimetic peptide (FGL) from the neural cell adhesion molecule (NCAM) that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP). Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by persistent CaMKII activation. These results provide a mechanistic link between facilitation of AMPA receptor synaptic delivery and improved hippocampal-dependent learning, induced by a pharmacological cognitive enhancer. ## Microscale AMPAR Reorganization and Dynamics of the Postsynaptic Density (2012) *The Journal of Neuroscience* [Full paper](https://www.jneurosci.org/content/32/21/7103.short) AMPA-type receptors (AMPARs) are glutamate-gated channels whose postsynaptic activation convey the major depolarization in brain excitatory neurotransmission. Trafficking of these receptors to and from synapses is tightly regulated in neurons and underlies long-lasting forms of synaptic plasticity. For example, export of AMPARs from the endoplasmic reticulum to the Golgi (Vandenberghe and Bredt, 2004) is suggested to contribute to the expression of certain types of synaptic plasticity (Broutman and Baudry, 2001). In addition, endocytosis removes AMPARs from synapses during LTD (Beattie et al., 2000) and in response to other stimuli (Man et al., 2000). Internalized AMPARs can be degraded in lysosomes or recycled back to the surface membrane (Ehlers, 2000; Gruenberg, 2001). This AMPAR sorting is regulated by synaptic activity (Ehlers, 2000) and provides the local intracellular pool of AMPARs needed for LTP expression (Park et al., 2004). AMPARs also undergo constitutive trafficking that involves both exocytic delivery from intracellular compartments (Gerges et al., 2006) and fast exchange with surface extrasynaptic receptors through lateral diffusion (Tardin et al., 2003). Still, knowledge is lacking regarding the organization and regulation of AMPARs within the postsynaptic density (PSD) and the events triggering their repositioning. ## Spines, Plasticity, and Cognition in Alzheimer's Model Mice (2012) *Neural Plasticity* [Full paper](https://www.hindawi.com/journals/np/2012/319836/) The pathological hallmarks of Alzheimer's disease (AD)—widespread synaptic and neuronal loss and the pathological accumulation of amyloid-beta peptide (Aβ) in senile plaques, as well as hyperphosphorylated tau in neurofibrillary tangles—have been known for many decades, but the links between AD pathology and dementia and effective therapeutic strategies remain elusive. Transgenic mice have been developed based on rare familial forms of AD and frontotemporal dementia, allowing investigators to test in detail the structural, functional, and behavioral consequences of AD-associated pathology. Here, we review work on transgenic AD models that investigate the degeneration of dendritic spine structure, synaptic function, and cognition. Together, these data support a model of AD pathogenesis in which soluble Aβ initiates synaptic dysfunction and loss, as well as pathological changes in tau, which contribute to both synaptic and neuronal loss. These changes in synapse structure and function as well as frank synapse and neuronal loss contribute to the neural system dysfunction which causes cognitive deficits. Understanding the underpinnings of dementia in AD will be essential to develop and evaluate therapeutic approaches for this widespread and devastating disease. ## WIP Is a Negative Regulator of Neuronal Maturation and Synaptic Activity (2011) *Cerebral Cortex* [Full paper](https://academic.oup.com/cercor/article/22/5/1191/282092?login=true) Wiskott–Aldrich syndrome protein (WASP) –interacting protein (WIP) is an actin-binding protein involved in the regulation of actin polymerization in cells, such as fibroblasts and lymphocytes. Despite its recognized function in non-neuronal cells, the role of WIP in the central nervous system has not been examined previously. We used WIP-deficient mice to examine WIP function both in vivo and in vitro. We report here that WIP−/− hippocampal neurons exhibit enlargement of somas as well as overgrowth of neuritic and dendritic branches that are more evident in early developmental stages. Dendritic arborization and synaptogenesis, which includes generation of postsynaptic dendritic spines, are actin-dependent processes that occur in parallel at later stages. WIP deficiency also increases the amplitude and frequency of miniature excitatory postsynaptic currents, suggesting that WIP−/− neurons have more mature synapses than wild-type neurons. These findings reveal WIP as a previously unreported regulator of neuronal maturation and synaptic activity. ## Layer-specific alterations to CA1 dendritic spines in a mouse model of Alzheimer's disease (2010) *Hippocampus* [Full paper](https://onlinelibrary.wiley.com/doi/abs/10.1002/hipo.20861) Why memory is a particular target for the pathological changes in Alzheimer's Disease (AD) has long been a fundamental question when considering the mechanisms underlying this disease. It has been established from numerous biochemical and morphological studies that AD is, at least initially, a consequence of synaptic malfunction provoked by Amyloid β (Aβ) peptide. APP/PS1 transgenic mice accumulate Aβ throughout the brain, and they have therefore been employed to investigate the effects of Aβ overproduction on brain circuitry and cognition. Previous studies show that Aβ overproduction affects spine morphology in the hippocampus and amygdala, both within and outside plaques (Knafo et al., (2009) Cereb Cortex 19:586-592; Knafo et al., (in press) J Pathol). Hence, we conducted a detailed analysis of dendritic spines located in the stratum oriens and stratum radiatum of the CA1 hippocampal subfield of APP/PS1 mice. Three-dimensional analysis of 18,313 individual dendritic spines revealed a substantial layer-specific decrease in spine neck length and an increase in the frequency of spines with a small head volume. Since dendritic spines bear most of the excitatory synapses in the brain, changes in spine morphology may be one of the factors contributing to the cognitive impairments observed in this AD model. © 2010 Wiley-Liss, Inc. ## PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression (2010) *EMBO Journal* [Full paper](https://www.embopress.org/doi/full/10.1038/emboj.2010.160) Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is an important regulator of phosphatidylinositol-(3,4,5,)-trisphosphate signalling, which controls cell growth and differentiation. However, PTEN is also highly expressed in the adult brain, in which it can be found in dendritic spines in hippocampus and other brain regions. Here, we have investigated specific functions of PTEN in the regulation of synaptic function in excitatory hippocampal synapses. We found that NMDA receptor activation triggers a PDZ-dependent association between PTEN and the synaptic scaffolding molecule PSD-95. This association is accompanied by PTEN localization at the postsynaptic density and anchoring within the spine. On the other hand, enhancement of PTEN lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses. This activity is specifically required for NMDA receptor-dependent long-term depression (LTD), but not for LTP or metabotropic glutamate receptor-dependent LTD. Therefore, these results reveal PTEN as a regulated signalling molecule at the synapse, which is recruited to the postsynaptic membrane upon NMDA receptor activation, and is required for the modulation of synaptic activity during plasticity. ## Morphological alterations to neurons of the amygdala and impaired fear conditioning in a transgenic mouse model of Alzheimer's disease (2009) *Journal of Pathology* [Full paper](https://onlinelibrary.wiley.com/doi/abs/10.1002/path.2565) Patients with Alzheimer's disease (AD) suffer from impaired memory and emotional disturbances, the pathogenesis of which is not entirely clear. In APP/PS1 transgenic mice, a model of AD in which amyloid β (Aβ) accumulates in the brain, we have examined neurons in the lateral nucleus of the amygdala (LA), a brain region crucial to establish cued fear conditioning. We found that although there was no neuronal loss in this region and Aβ plaques only occupy less than 1% of its volume, these mice froze for shorter times after auditory fear conditioning when compared to their non-transgenic littermates. We performed a three-dimensional analysis of projection neurons and of thousands of dendritic spines in the LA. We found changes in dendritic tree morphology and a substantial decrease in the frequency of large spines in plaque-free neurons of APP/PS1 mice. We suggest that these morphological changes in the neurons of the LA may contribute to the impaired auditory fear conditioning seen in this AD model. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. ## PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane (2009) *Nature Neuroscience* [Full paper](https://www.nature.com/articles/nn.2462) Despite their low abundance, phosphoinositides are critical regulators of intracellular signaling and membrane compartmentalization. However, little is known of phosphoinositide function at the postsynaptic membrane. Here we show that continuous synthesis and availability of phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the postsynaptic terminal is necessary for sustaining synaptic function in rat hippocampal neurons. This requirement was specific for synaptic, but not extrasynaptic, AMPA receptors, nor for NMDA receptors. PIP3 downregulation impaired PSD-95 accumulation in spines. Concomitantly, AMPA receptors became more mobile and migrated from the postsynaptic density toward the perisynaptic membrane within the spine, leading to synaptic depression. Notably, these effects were only revealed after prolonged inhibition of PIP3 synthesis or by direct quenching of this phosphoinositide at the postsynaptic cell. Therefore, we conclude that a slow, but constant, turnover of PIP3 at synapses is required for maintaining AMPA receptor clustering and synaptic strength under basal conditions. ## Widespread Changes in Dendritic Spines in a Model of Alzheimer's Disease (2009) *Cerebral Cortex* [Full paper](https://academic.oup.com/cercor/article/19/3/586/431357?login=true) The mechanism by which dementia occurs in patients with Alzheimer's disease (AD) is not known. We assessed changes in hippocampal dendritic spines of APP/PS1 transgenic mice that accumulate amyloid beta throughout the brain. Three-dimensional analysis of 21 507 dendritic spines in the dentate gyrus, a region crucial for learning and memory, revealed a substantial decrease in the frequency of large spines in plaque-free regions of APP/PS1 mice. Plaque-related dendrites also show striking alterations in spine density and morphology. However, plaques occupy only 3.9% of the molecular layer volume. Because large spines are considered to be the physical traces of long-term memory, widespread decrease in the frequency of large spines likely contributes to the cognitive impairments observed in this AD model. ## Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology (n.d.) Background Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca2+ homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction. Methods To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests. Results In neuronal cultures, amyloid-beta (Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aβ plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load. Conclusions The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment. # Awards & honors ## National Research Council Annual tribute to its scientists (2017) ## Woman of the year in medicine (2016) By Women Magazine ## National Research Council Annual tribute to its scientists (2012) In 12th of July 2012 the National Research Council (CSIC) paid tribute to its scientists that were awarded a scientific prize in 2011-2012. ## Sieratzki Prize For Advances in Neuroscience (2012) The Sieratzki Prize is awarded annually to outstanding young Israeli scientists who have significantly impacted the field of neuroscience. FROM TEL AVIV UNIVERSITY WEBSITE: “The 2012 Sieratzki Prize for Advances in Neuroscience was awarded by Tel Aviv University Governor Barbara Sieratzki and son Dr. Jechil (Harry) Sieratzki to Dr. Shira Knafo of the Severo Ochoa Center for Molecular Biology (CSIC) in Madrid and Dr. Adrian Israelson of the Ludwig Institute for Cancer Research at the University of California. The recipients each gave a fascinating presentation of their research topics.“ # News Lab news, paper drops, and press coverage. ## New article in Molecular Psychiatry (2024): A mechanism linking anxiety to testosterone has been discovered. *2024 · Molecular Psychiatry · Uncategorized* [Source](https://www.nature.com/articles/s41380-023-02361-z) A groundbreaking study conducted by the Molecular Cognitive Lab, led by Professor Shira Kanfo, and published in the prestigious journal Molecular Psychiatry, has unveiled a significant link between anxiety disorders and a brain receptor known as TACR3, as well as testosterone. Anxiety is a common response to stress, but for those dealing with anxiety disorders, it can significantly impact daily life. Clinical evidence has hinted at a close connection between low testosterone levels and anxiety, particularly in men with hypogonadism, a condition characterized by reduced sexual function. However, the precise nature of this relationship has remained unclear until now. The study commenced with a fascinating discovery: male rodents exhibiting exceedingly high anxiety levels had notably lower levels of a specific receptor called TACR3 in their hippocampus. The hippocampus is a brain region closely associated with learning and memory processes. TACR3 is part of the tachykinin receptor family and responds to a substance known as neurokinin. This observation piqued the researchers' curiosity and was the foundation for an in-depth investigation into the link between TACR3 deficiency, sex hormones, anxiety, and synaptic plasticity. The rodents were classified based on their behavior in a standard elevated plus maze test measuring anxiety levels. Subsequently, their hippocampi were isolated and underwent gene expression analysis to identify genes with differential expression between rodents with extremely low anxiety and those with severe anxiety. One gene that stood out was TACR3. Previous research had revealed that mutations in genes associated with TACR3 led to a condition known as "congenital hypogonadism," resulting in reduced sex hormone production, including testosterone. Notably, young men with low testosterone often experience delayed sexual development, accompanied by depression and heightened anxiety. This led researchers to investigate the role of TACR3 in anxiety further. Researchers successfully harnessed two innovative tools crafted in their laboratory in the study. The first, known as FORTIS, boasts the remarkable ability to detect changes in AMPA receptors within living neurons. By utilizing FORTIS, they demonstrated that inhibiting TACR3 resulted in a sharp increase in AMPA receptors on the cell surface, disrupting the parallel process of long-term synaptic strengthening, known as LTP. The second pioneering tool employed was a novel application of cross-correlation to measure neuronal connectivity within a multi-electrode array system. This tool played a pivotal role in uncovering the profound impact of TACR3 manipulations on synaptic plasticity. Importantly, it revealed that deficiencies stemming from TACR3 inactivity could be efficiently rectified through testosterone administration, offering hope for novel approaches to address challenges related to anxiety associated with testosterone deficiency. In conclusion, this research positions TACR3 as a central player in bridging anxiety and testosterone. The researchers have unraveled the complex mechanisms behind anxiety and opened avenues for novel therapies, including testosterone treatments, that could improve the quality of life for individuals grappling with sexual development disorders and associated anxiety and depression ## New article in Brain (2022): Striatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism *2022 · Brain · New Article* [Source](https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awac087/6542505?redirectedFrom=fulltext) Synaptic impairment might precede neuronal degeneration in Parkinson’s disease. However, the intimate mechanisms altering synaptic function by the accumulation of presynaptic α-synuclein in striatal dopaminergic terminals before dopaminergic death occurs, have not been elucidated. Our aim is to unravel the sequence of synaptic functional and structural changes preceding the symptomatic dopaminergic cell death. As such, we evaluated the temporal sequence of functional and structural changes at striatal synapses before parkinsonian motor features appear in a rat model of progressive dopaminergic death induced by overexpression of the human mutated A53 T α-synuclein in the substantia nigra pars compacta, a protein transported to these synapses. SWATH-MS proteomics identified deregulated proteins involved firstly in energy metabolism and later, in vesicle cycling and autophagy. After protein deregulation and when α-synuclein accumulated at striatal synapses, alterations to mitochondrial bioenergetics were observed using a Seahorse XF96 analyser. Sustained dysfunctional mitochondrial bioenergetics is followed by a decrease in the number of dopaminergic terminals, morphological and ultrastructural alterations, and an abnormal accumulation of autophagic/endocytic vesicles inside the remaining dopaminergic fibres evident by electron microscopy. The total mitochondrial population remained unchanged whereas the number of ultrastructurally damaged mitochondria increases as the pathological process evolves. We also observed ultrastructural signs of plasticity within glutamatergic synapses before the expression of motor abnormalities, such as a reduction in axospinous synapses and an increase in perforated post-synaptic densities. Overall, we found that a synaptic energetic failure and accumulation of dysfunctional organelles occur sequentially at the dopaminergic terminals as the earliest events preceding structural changes and cell death. We also identify key proteins involved in these earliest functional abnormalities that may be modulated and serve as therapeutic targets to counterbalance the degeneration of dopaminergic cells in order to delay or prevent the development of Parkinson’s disease. ## New article in Frontiers in Synaptic Neuroscience (2021): Aberrant Synaptic PTEN in Symptomatic Alzheimer’s Patients May Link Synaptic Depression to Network Failure *2021 · Frontiers in Synaptic Neuroscience · New Article* [Source](https://internal-journal.frontiersin.org/articles/10.3389/fnsyn.2021.683290/full) In Alzheimer’s disease (AD), Amyloid β (Aβ) impairs synaptic function by inhibiting long-term potentiation (LTP), and by facilitating long-term depression (LTD). There is now evidence from AD models that Aβ provokes this shift toward synaptic depression by triggering the access to and accumulation of PTEN in the postsynaptic terminal of hippocampal neurons. Here we quantified the PTEN in 196,138 individual excitatory dentate gyrus synapses from AD patients at different stages of the disease and from controls with no neuropathological findings. We detected a gradual increase of synaptic PTEN in AD brains as the disease progresses, in conjunction with a significant decrease in synaptic density. The synapses that remain in symptomatic AD patients are more likely to be smaller and exhibit fewer AMPA receptors (AMPARs). Hence, a high Aβ load appears to strongly compromise human hippocampal synapses, as reflected by an increase in PTEN, inducing a loss of AMPARs that may eventually provoke synaptic failure and loss. ## New article in Translational Psychiatry (2021): FORTIS: a live-cell assay to monitor AMPA receptors using pH-sensitive fluorescence tags *2021 · Translational Psychiatry · New Article* [Source](https://www.nature.com/articles/s41398-021-01457-w) The real-time live fluorescent monitoring of surface AMPA receptors (AMPARs) could open new opportunities for drug discovery and phenotypic screening concerning neuropsychiatric disorders. We have developed FORTIS, a tool based on pH sensitivity capable of detecting subtle changes in surface AMPARs at a neuronal population level. The expression of SEP-GluA1 or pHuji-GluA1 recombinant AMPAR subunits in mammalian neurons cultured in 96-well plates enables surface AMPARs to be monitored with a microplate reader. Thus, FORTIS can register rapid changes in surface AMPARs induced by drugs or genetic modifications without having to rely on conventional electrophysiology or imaging. By combining FORTIS with pharmacological manipulations, basal surface AMPARs, and plasticity-like changes can be monitored. We expect that employing FORTIS to screen for changes in surface AMPARs will accelerate both neuroscience research and drug discovery. ## New article in Cerebral Cortex (2020): PTEN Activity Defines an Axis for Plasticity at Cortico-Amygdala Synapses and Influences Social Behavior *2020 · Cerebral Cortex · New Article* [Source](https://pubmed.ncbi.nlm.nih.gov/31240311/) Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor and autism-associated gene that exerts an important influence over neuronal structure and function during development. In addition, it participates in synaptic plasticity processes in adulthood. As an attempt to assess synaptic and developmental mechanisms by which PTEN can modulate cognitive function, we studied the consequences of 2 different genetic manipulations in mice: presence of additional genomic copies of the Pten gene (Ptentg) and knock-in of a truncated Pten gene lacking its PDZ motif (Pten-ΔPDZ), which is required for interaction with synaptic proteins. Ptentg mice exhibit substantial microcephaly, structural hypoconnectivity, enhanced synaptic depression at cortico-amygdala synapses, reduced anxiety, and intensified social interactions. In contrast, Pten-ΔPDZ mice have a much more restricted phenotype, with normal synaptic connectivity, but impaired synaptic depression at cortico-amygdala synapses and virtually abolished social interactions. These results suggest that synaptic actions of PTEN in the amygdala contribute to specific behavioral traits, such as sociability. Also, PTEN appears to function as a bidirectional rheostat in the amygdala: reduction in PTEN activity at synapses is associated with less sociability, whereas enhanced PTEN activity accompanies hypersocial behavior. ## New article in Pharmaceutical Research (2020): Preformulation studies of a stable PTEN-PDZ lipopeptide able to cross an in vitro blood-brain-barrier model as a potential therapy for Alzheimer’s disease *2020 · Pharmaceutical Research · New Article* [Source](https://pubmed.ncbi.nlm.nih.gov/32888078/) Amyloid β (Aβ) drives the accumulation of excess Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) at synapses, inducing synaptic depression and perturbing memory. This recruitment of PTEN to synapses in response to Aβ drives its interaction with PSD95/Disc large/Zonula occludens-1 (PDZ) proteins and, indeed, we previously showed that an oligo lipopeptide (PTEN-PDZ) capable of blocking such PTEN:PDZ interactions rescues the synaptic and cognitive deficits in a mouse model of Alzheimer’s disease. Hence, the PTEN:PDZ interaction appears to be crucial for Aβ-induced synaptic and cognitive impairment. Here we have evaluated the feasibility of using PTEN-PDZ lipopeptides based on the human/mouse PTEN C-terminal sequence, testing their stability in biological fluids, their cytotoxicity, their ability to self-assemble and their in vitro blood-brain barrier (BBB) permeability. Myristoyl or Lauryl tails were added to the peptides to enhance their cell permeability. Lipopeptides self assembly was assessed using electron microscopy and the thioflavin T assay. Stability studies in mouse plasma (50%), intestinal washing, brain and liver homogenates as well as permeability studies across an all human 2D blood-brain barrier model prepared with human cerebral endothelial cells (hCMEC/D3) and human astrocytes (SC-1800) were undertaken. The mouse lauryl peptide displayed enhanced overall stability in plasma, ensuring a longer half-life in circulation that meant there were larger amounts available for transport across the BBB (Papp0-4h: 6.28 ± 1.85 × 10−6 cm s−1). This increased availability, coupled to adequate BBB permeability, makes this peptide a good candidate for therapeutic parenteral (intravenous, intramuscular) administration and nose-to-brain delivery. ## New article in Nature Communications (2019): Evidence of conditioned behavior in amoebae *2019 · Nature Communications · New Article* [Source](https://www.nature.com/articles/s41467-019-11677-w) Associative memory is the main type of learning by which complex organisms endowed with evolved nervous systems respond efficiently to certain environmental stimuli. It has been found in different multicellular species, from cephalopods to humans, but never in individual cells. Here we describe a motility pattern consistent with associative conditioned behavior in the microorganism Amoeba proteus. We use a controlled direct-current electric field as the conditioned stimulus, and a specific chemotactic peptide as the unconditioned stimulus. The amoebae are capable of linking two independent past events, generating persistent locomotion movements that can prevail for 44 min on average. We confirm a similar behavior in a related species, Metamoeba leningradensis. Thus, our results indicate that unicellular organisms can modify their behavior during migration by associative conditioning. ## New review paper (2018): Peptides acting as cognitive enhancers *2018 · Science Direct · Review* [Source](https://www.sciencedirect.com/science/article/pii/S0306452217307212#f0005) The aim of this paper is to present an overview of three peptides that, by improving synaptic function, enhance learning and memory in laboratory rodents. We summarize their structure, their mechanisms of action, and their effects on synaptic and cognitive function. First we describe FGL, a peptide derived from the neural cell adhesion molecule which improves cognition by the activation of the PKC pathway that triggers an activity-dependent delivery of AMPA receptors to the synapses. Then we describe PTD4-PI3KAc peptide that by activating PI3K signaling pathway it promotes synapse and spine formation and enhances hippocampal dependent memory. Lastly, we describe a new peptide derived from the well-known tumor suppressor PTEN that prevents pathological interactions between PTEN and PDZ proteins at synapses during exposure to Amyloid beta. This action prevents memory deterioration in mouse model of Alzheimer’s disease. Together, this review indicates how learning and memory can be improved by manipulating synaptic function and number through pharmacological treatment with peptides, and it establishes synaptic function as a valid target for cognitive enhancement. ## New review article in Trends in Neuroscience (2017): PTEN: local and global modulation of neuronal function in health and disease *2017 · Science Direct · Review* [Source](https://www.sciencedirect.com/science/article/pii/S016622361630176X#fig0005) Phosphatase and tensin homolog deleted on chromosome ten (PTEN) controls neuronal growth and synaptic function not only during embryonic and postnatal development but also throughout adult life. Direct recruitment of PTEN to the postsynaptic membrane drives synaptic depression. PTEN’s action at synapses is hijacked and exacerbated in response to amyloid β in Alzheimer’s disease (AD). Preventing excessive recruitment of PTEN to synapses ameliorates cognitive function in AD mouse models. Autistic disorders associated with PTEN loss of function are not exclusively the consequence of a defective neurodevelopmental program but may also reflect ongoing failures in synaptic depression because of insufficient PTEN activity at synapses. ## New paper in Nature Neuroscience (2016): PTEN recruitment controls synaptic and cognitive function in Alzheimer’s models *2016 · Nature Neuroscience · New Paper* [Source](https://pubmed.ncbi.nlm.nih.gov/26780512/) Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer’s disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer’s disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling. ## New book, Cognitive Enhancement, 1st Edition (Elsevier) *214 · Amazon · New Book* [Source](https://www.amazon.com/Cognitive-Enhancement-Pharmacologic-Environmental-Genetic-ebook/dp/B00RMXW2B8) Review on this book “This is an important and timely addition to the multidisciplinary field that has arisen to address the problems of cognitive decline and the competition for limited resources. Score: 98 – 5 Stars” This new book contains a vast amount of information regarding traditional and modern strategies aimed at enhancing cognitive function, both in animals and humans. The editors made an effort to make this book accessible to the general public, although some of the chapters may be more scientifically orientated than others. Nevertheless, the general goal of this book is to bring together the bulk of information available in this field, in the hope that this will eventually help scientists to develop new, more efficient approaches to treat cognitive impairment. What is Cognitive enhancement? “Cognitive enhancement” is commonly associated with drug use or the use of devices to improve cognition. In this book we present an up-to-date overview of drugs, environmental conditions, and genetic factors related to cognitive enhancement in health and disease, gathering multidisciplinary knowledge and tools that will enable a further understanding of the topic. The chapters of the book have been written by top neuroscientists and they look in depth at a number of the traditional and cutting-edge technologies that are currently studied and employed in experimental animals and sometimes, in humans. Understanding mechanisms of normal cognitive function helps to develop new cognitive enhancers. One of the most common approaches to develop new cognitive enhancers is to identify the pathways involved in learning and memory, and to test activators specific to these pathways. Having understood the signaling pathways that globally modulate learning and memory, it is essential to uncover the specific molecular and synaptic events mediating cognitive function. Accordingly, sophisticated molecular and electrophysiological tools based on the idea that facilitating synaptic plasticity may eventually lead to better cognitive function, a result that can be achieved by manipulating the activity of neurotransmitter receptors. How can environmental and epigenetic factors improve cognition? Control over the environment may represent a physiological approach to cognitive enhancement, focusing on how the incredible plasticity of the brain is used to evolve behaviors that accommodate the inherent uncertainty and probabilistic nature of the environment. We discuss how this plasticity requires a constant interaction between the genome and the environment, with epigenetic mechanisms. What can we learn from smart transgenic mice? We describes how cognitive functions are enhanced in some transgenic mice. Understanding the mechanisms of memory enhancement in these ‘smart mice’ is an important tool to elucidate the basic mechanisms underlying learning and memory, as well as to develop treatments for cognitive disorders. Can viruses be used to enhance learning and memory? Viral gene therapy involves delivering genes of interest into the specific brain region to either protect neurons or to enhance neural regeneration, thereby promoting cognitive function. Controlling cognition with light Optogenetics is an innovative method that permits real-time control of genetically-defined neuronal populations using light-sensitive proteins. The incorporation of optogenetic tools into the field of learning and memory can be used for memory generation and cognitive enhancement. Stem cells implantation as a promising approach to treat memory problems We describe how multipotent stem cells within the adult brain play a critical role in cognition and the strategies to favor neural stem cell populations within key brain regions that are being developed to enhance cognition in rodents. Moreover, the brain’s capacity for plasticity and regeneration is reviewed, along with the potential role of endogenous neurogenesis and stem cell transplantation to augment this capacity. What about Alzheimer’s disease and other neuropsychiatric disorders? We describe the cognition-enhancing manipulations overcoming the cognitive deficits related to Alzheimer’s disease. Unfortunately, in most cases the strategies that have proven successful in rodents tend to fail in human beings. In some cases, the failure of the treatment can be easily traced, as when the treatment produced significant side-effects. However, in most cases there is no ready explanation for failure. We also review different pharmaceutical treatments to reverse neurocognitive deficits frequently found in several neuropsychiatric disorders, including: Attention deficit hyperactive disorder (ADHD), schizophrenia, bipolar disorder, Post-traumatic stress disorder (PTSD), and depression. What is really going on in human patients? We summarize the approaches to enhance cognitive capabilities in humans using pharmaceuticals, nutrition, physical exercise, sleep, meditation, mnemonic strategies, computer training and brain stimulation. The mixed evidence for the efficacy of many pharmaceutical drugs currently used for cognitive enhancement is summarized, while a growing body of evidence for several non-pharmacological interventions indicates reliable cognition enhancing effects. In this respect, we provide valuable data on the use of non-invasive brain stimulation for cognitive enhancement, such astranscranial direct current stimulation (tDCS). The evidence of the safety, beneficial impacts and cost-benefit ratio of these techniques at the individual and societal level are discussed in detail, along with the mechanisms and physiological effects of tDCS, and its effects on human cognition. Science fiction is here! We describe possible scenarios that may currently sound unrealistic yet that serve to reflect on the danger of unregulated use of cognitive enhancers. This chapter explains why and how authorities should strictly control the prescription of cognitive enhancers, adapting state laws to these new technologies. See more about this book in Elsevier website and in Ikerbasque press release. # On our work Third-party coverage of the lab's research. ## Nature Portfolio: Unveiling the Connection Between Testosterone and Anxiety *https://communities.springernature.com/posts/unveiling-the-connection-between-testosterone-and-anxiety* [Source](https://communities.springernature.com/posts/unveiling-the-connection-between-testosterone-and-anxiety) Anxiety is a typical stress response, but it can become overwhelming for those grappling with anxiety disorders, significantly impacting their daily lives. Research indicates a close association between low testosterone levels and anxiety, even though the precise nature of this relationship remains somewhat enigmatic.  Clinical evidence hints at the potential of testosterone in alleviating anxiety and depression, particularly in males with low testosterone due to hypogonadism. However, this connection has lacked a comprehensive explanation until now. Our Scientific Journey: We embarked on an intriguing scientific quest to decipher the intricate relationship between anxiety and testosterone—a question that has puzzled researchers for years. How It All Started: Our journey began with a captivating discovery: rats prone to anxiety exhibited lower levels of a specific receptor called Tachykinin receptor 3 (TACR3) in their ventral hippocampus. TACR3 is part of a group of receptors known as tachykinin receptors, and it responds to a substance called neurokinin B (NKB). This observation sparked our curiosity and set the stage for a deep exploration into the connections between TACR3 deficiency, sex hormones, anxiety, and synaptic plasticity. Our Investigation: We began by categorizing the rats based on their behavior in an elevated plus maze—a commonly used test to measure rodent anxiety levels. We then isolated the rats' hippocampi and used gene expression analysis to identify genes that behaved differently in rats with very low anxiety compared to those with severe anxiety. One gene that stood out was tacr3. Further research revealed that mutations in genes related to neurokinin B (TAC3) and its receptor (TACR3) lead to a condition known as non-syndromic normosmic congenital hypogonadotropic hypogonadism (CHH). CHH results in a lack of gonadal hormones, including lower testosterone levels. Notably, young men with low testosterone often experience depression and anxiety, prompting us to explore the role of TACR3 in anxiety. Our research involved studying where TACR3 is found in the rat brain, how its expression changes during growth, and how sex hormones influence its presence in the hippocampus. We also examined the effects of drugs that can modulate TACR3 on synaptic plasticity. Additionally, we cloned the tacr3 gene to overexpress it in our neurons. In our research, we harnessed the power of two innovative tools, both of which were meticulously crafted within our laboratory. The first tool, known as FORTIS, boasts the remarkable ability to detect alterations in surface AMPA receptors within living neurons. Through the utilization of FORTIS, we successfully demonstrated that the TACR3 receptor antagonist Osanetant yields a profound increase in surface AMPA receptors while concurrently thwarting the process of Long-Term Potentiation (LTP). Our second pioneering tool involves the ingenious application of cross-correlation as a metric for assessing connectivity among neurons. This invaluable instrument played a pivotal role in uncovering the substantial impact of TACR3 manipulations on neural connectivity. Importantly, it revealed that deficiencies arising from an inactive TACR3 can be effectively rectified through the administration of testosterone. What We Discovered: Among our findings, one discovery shone brightly: we uncovered that sex hormones, particularly testosterone, have a remarkable ability to influence the expression of TACR3 in the hippocampus. This dynamic interplay between TACR3 and sex hormones holds profound implications for anxiety-like behaviors in living organisms. As we delved deeper into our exploration, we stumbled upon another intriguing observation. Rats with heightened anxiety levels were missing a crucial element in their hippocampus-long-term potentiation (LTP). LTP is a phenomenon that signifies the strengthening of neural connections, crucial for learning and memory. However, in severely anxious rats lacking TACR3, something remarkable occurred. Connectivity became more robust, preventing further strengthening in the form of LTP. We also discovered that modulating TACR3, either through drugs or molecular tools, profoundly affected synaptic plasticity. This revelation adds a new layer of understanding to the intricate relationship between TACR3, anxiety, and neural connectivity. What makes this discovery even more exciting is the potential for testosterone treatment to counteract these plasticity changes, offering hope for innovative approaches to address anxiety-related challenges. Beyond Anxiety: Our research goes beyond anxiety dynamics. It also sheds light on non-syndromic normosmic congenital hypogonadotropic hypogonadism - a condition linked to mutations in TACR3 or TAC3 genes, resulting in reduced gonadal hormone production and lower testosterone levels. These findings hold promise for individuals dealing with sexual dysfunction, depression, and heightened anxiety, emphasizing the potential of testosterone treatments to enhance their quality of life. Our Conclusion: In summary, our study positions TACR3 as a pivotal link connecting anxiety and testosterone. We've unraveled the intricate mechanisms behind anxiety and opened the door to innovative treatments involving testosterone and the modulation of synaptic plasticity. Our findings provide valuable insights into the complexity of anxiety and offer hope for future therapeutic approaches. Analysis of hippocampal gene expression in rats with diverse anxiety-like behaviors. ## Science Signaling: PTEN contributes to Alzheimer’s disease *science.org* [Source](https://www.science.org/lookup/doi/10.1126/scisignal.aaf5520) The phosphatase PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)–AKT pathway by converting the phospholipid PIP3 to PIP2. PIP3-mediated PI3K-AKT signaling in neurons increases synaptic strength of active synapses, a phenomenon called long-term potentiation (LTP). Mutations in PTEN are associated with various neurological disorders, such as autism and seizures. In Alzheimer’s disease (AD), accumulation of the peptide β-amyloid (Aβ), produced from the product of the APP gene, is associated with depressed synaptic activity and neuronal cell death in the hippocampus and consequently cognitive dysfunction in the patient. Knafo et al. found that PTEN linked Aβ to postsynaptic depression (see also Frere and Slutsky). Transgenic whole-body overexpression of Pten in mice suppressed hippocampal synaptic activity, and adding Aβ to slices from these mice had no further depressive effect. PTEN inhibition with the drug VO-OHpic prevented Aβ-induced decreases in synaptic transmission and LTP in hippocampal slices and rescued cognitive function in a mouse model of AD. In hippocampal slices from a different mouse model, current through the glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type (AMPARs), but not glutamate receptors of the N-methyl-D-aspartate type (NMDARs), were reduced in neurons overexpressing App. Either PTEN inhibitors or overexpression of a dominant-negative PTEN mutant increased AMPAR currents in those neurons. However, PTEN inhibition had no effect on the amounts of amyloid precursor protein (APP) or Aβ in the mouse models tested. Together, these results suggested that PTEN may act downstream of Aβ in a common pathway to depress synaptic transmission. ## Nature Neuroscience: Targeting PTEN interactions for Alzheimer's disease *nature.com* [Source](https://www.nature.com/articles/nn.4248) Depression of AMPA receptor–mediated synaptic currents and impairment of long-term potentiation, triggered by amyloid-β, are the hallmarks of Alzheimer's pathophysiology. These dysfunctions are now linked to upregulated PDZ domain–dependent PTEN translocation to spines, contributing to cognitive deficits in model mice. ## AlzForum: PTEN Makes Aβ Depressingly Toxic *alzforum.org* [Source](https://www.alzforum.org/news/research-news/pten-makes-av-depressingly-toxic) Too much Aβ weakens neural synapses by favoring long-term depression, but how? A report published January 18 in Nature Neuroscience suggests that the peptide does so by hijacking the neuron’s own mechanisms of synaptic plasticity. Scientists led by José Esteban from the Spanish Research Council (CSIC), César Venero from the National Distance Education University in Madrid (UNED), and Shira Knafo of the University of the Basque Country find that Aβ helps recruit more than the usual amount of PTEN—a protein that previously has been implicated in long-term depression—to the postsynaptic membrane. This, they report, tips the balance away from long-term potentiation and toward depression. The findings give new insight into how Aβ might mess with cognition. “We knew that plasticity was out of balance in Alzheimer’s disease, but we didn’t know why,” Esteban told Alzforum. “This is one mechanism that explains how it is impaired.” ## New study reveals drugs that may improve memory and learning *dailyrecord.co.uk* [Source](https://www.dailyrecord.co.uk/news/science-technology/new-study-reveals-drugs-that-may-improve-1117515) DRUGS that improve connections between nerve cells in the brain may be able to improve people's memory and help understand disorders such as Alzheimer's disease, scientists have revealed. ## New Protein Improves Memory, Offers Insight Into Learning Process *psychologytoday.com* [Source](https://www.psychologytoday.com/ca/blog/you-illuminated/201203/new-protein-improves-memory-offers-insight-learning-process) A recent study in PLoS Biology should give hope to the forgetful. A collaborative research group in Europe, spanning Spain, Switzerland and Denmark, developed a small protein called FGL that enhances memory formation and learning in rats, and now they have some explanation as to why. The study's authors, led by Shira Knafo, César Venero and José Esteban, attribute the improvement from FGL to better connections—and ability to strengthen those connections—between neurons. This knowledge may eventually improve treatment of some disorders, as the authors explain that these "mechanisms are thought to be responsible for multiple cognitive deficits, such as autism and Alzheimer's disease" ## Peptide Sparks Synaptic Plasticity, Improves Memory in Rodents *alzforum.org* [Source](https://www.alzforum.org/news/research-news/peptide-sparks-synaptic-plasticity-improves-memory-rodents) A small peptide called FGL boosts learning and memory when administered to rodents, and is poised to begin clinical trials in Alzheimer’s disease patients this year. Intriguingly, FGL sharpens memory in wild-type rats as well as in several disease models. While prior studies suggested that the heightened learning resulted from improved synaptic plasticity in the hippocampus (see Dallérac et al., 2011), the mechanism was unclear. Now, in the February 21 PLoS Biology, researchers led by José Esteban at the Universidad Autónoma de Madrid, Spain, detail the signaling pathway behind this effect. They report that FGL treatment stimulates activity-dependent delivery of glutamate receptors to synapses, leading to a long-term enhancement of synaptic transmission. # Videos & interviews ## Video *Hebrew* [Watch on YouTube](https://www.youtube.com/watch?v=SNwoJmE55qY) ## Approaches - Molecular Cognition Laboratory *Approaches · English* [Watch on YouTube](https://www.youtube.com/watch?v=Jm2-kkVU_tE) ## Presenation video *About our Lab · English* [Watch on YouTube](https://www.youtube.com/watch?v=Rwqe0XS5z4g) ## ראיון עם גבי גזית 2017 *Imaging · Hebrew* [Watch on YouTube](https://youtu.be/rCVZQcgaYi4) ## ראיון עם רוני קובן *Imaging · Hebrew* [Watch on YouTube](https://youtu.be/dx8wSRTqAxw) ## ראיון עם רינה מצליח *Interviews · Hebrew* [Watch on YouTube](https://youtu.be/PsafeCTOyEo) ## שלושה שיודעים עם שרון קנטור - ראיון עם פרופ שירה כנפו [Watch on YouTube](https://www.youtube.com/watch?v=SNwoJmE55qY) ## שלושה שיודעים עם שרון קנטור - ראיון עם פרופ שירה כנפו שלושה שיודעים עם שרון קנטור - ראיון עם פרופ שירה כנפו ## שלושה שיודעים ראיון עם דודו ארז *Hebrew* [Watch on YouTube](https://youtu.be/hLSvcLjUYYE) # Book ## Cognitive Enhancement *Pharmacologic, Environmental and Genetic Factors * [View on Amazon](https://www.amazon.com/Cognitive-Enhancement-Pharmacologic-Environmental-Genetic-ebook/dp/B00RMXW2B8) This new book contains a vast amount of information regarding traditional and modern strategies aimed at enhancing cognitive function, both in animals and humans. The editors made an effort to make this book accessible to the general public, although some of the chapters may be more scientifically orientated than others. Nevertheless, the general goal of this book is to bring together the bulk of information available in this field, in the hope that this will eventually help scientists to develop new, more efficient approaches to treat cognitive impairment. # Hebrew media coverage כתבות וראיונות בעברית ## זיכרון בלי מוח: גם יצורים חד-תאיים לומדים *ynet.co.il · 15/09/2019* [קרא עוד](https://www.ynet.co.il/articles/0,7340,L-5588805,00.html) חוקרים מישראל ומספרד גילו לראשונה שגם יצורים חד-תאיים מסוגלים לפתח למידה אסוציאטיבית ולשמר. החוקרים: "מקווים שהמחקר הזה יוביל לפתרון בעיות זיכרון כמו אלצהיימר" ## האם יש תרופה שתעשה אותנו חכמים יותר? *walla.co.il · 2017-10-08T00:00:00* [קרא עוד](https://healthy.walla.co.il/item/3087714) זוכרים את הסרט ללא גבולות? את אדי מורה לוקח כדור קטן ולפתע נהיה מבריק בצורה יוצאת דופן? אז מסתבר שהחזון הזה לא מאוד רחוק מהמציאות. אילו משפרים קוגניטיביים קיימים בשוק, ומה המחיר של השימוש בהם? פרופ' שירה כנפו, ראש מעבדה לקוגניציה מולקולרית, עם כל התשובות ## פרופ' שירה כנפו על פיתוח תרופות לשיפור מעבר האינפורמציה בין התאים במוח *maariv.co.il · 2017-11-07T00:00:00* [קרא עוד](https://103fm.maariv.co.il/programs/media.aspx?ZrqvnVq=HDIDLL&c41t4nzVQ=EE) פרופ' למדעי המוח באוניברסיטת חבל הבאסקים שירה כנפו מספרת על המחקר לפיתוח תרופות שיוכלו להעלות את רמת החוכמה שלנו על ידי שיפור של מעבר האינפורמציה בין התאים במוח - האזינו ## החוקרת מישראל שמובילה את המחקר על האלצהיימר *mako.co.il · 27/02/2016* [קרא עוד](https://www.mako.co.il/news-israel/health-q1_2016/Article-408eea3ad142351004.htm) פרופ' שירה כנפו  מובילה צוות מחקר בינלאומי שהגיע לפריצת דרך משמעותית בחקר האלצהיימר. נפגשנו איתה במעבדה בחיפה וגילינו שמה שמניע אותה הוא הרצון לעזור לאנשים בהתמודדות במחלה הקשה הזאת שפוגעת בכל המשפחה לא רק בחולה. פרס נובל?   היא לא חושבת על זה ## בשורה בתחום חקר המוח : אותר מנגנון "עוקף אלצהיימר" *walla.co.il · 2016-08-02T00:00:00* [קרא עוד](https://healthy.walla.co.il/item/2932991) המנגנון, שזוהה על ידי צוות חוקרים בינלאומי בראשותה של הישראלית פרופ' שירה כנפו, הופך תאי עצב לחסינים למחלה. בניסוי שבוצע בעכברים הצליחו החוקרים להשיב את מוחם החולה באלצהיימר לתפקוד מלא