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

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.

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.

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.

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.
Left, Heat maps showing the changes in SEP/pHuji-GluA1 as a function of pH and after the addition of ammonium chloride (NH4Cl). Each square represents the relative fluorescence in a single well (culture).

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.

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.

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.

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.

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