• Shira Knafo
  • Shira Knafo
  • Shira Knafo

  • Shira Knafo
  • Shira Knafo
  • Synaptic Manipulations
  • Cognitive Disorders
  • Brain Microcircuits
  • Alzheimer's Disease
  • Electrophysiology

Molecular Cognition Laboratory - Shira Knafo's Lab


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Aberrant Synaptic PTEN in Symptomatic Alzheimer’s Patients May Link Synaptic Depression to Network Failure


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.


Our New Trends in Neuroscience Paper:

PTEN: Local and Global Modulation of Neuronal Function in Health and Disease

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) was recently revealed to be a synaptic player during plasticity events in addition to its well-established role as a general controlling factor in cell proliferation and neuronal growth during development. Alterations of these direct actions of PTEN at synapses may lead to synaptic dysfunction with behavioral and cognitive consequences. A recent paradigmatic example of this situation, Alzheimer's disease (AD), is associated with excessive recruitment of PTEN into synapses leading to pathological synaptic depression. By contrast, some forms of autism are characterized by failure to weaken synaptic connections, which may be related to insufficient PTEN signaling. Understanding the modulation of synaptic function by PTEN in these pathologies may contribute to the development of new therapies.


Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN)-Mediated Synaptic Dysfunction in Alzheimer's Disease and Autism. (A) The presence of amyloid β induces exaggerated synaptic recruitment of PTEN. The triggering mechanism remains unknown but requires NMDA receptor activation and relies on PDZ-dependent interactions, similar to physiological long-term depression (LTD). The sustained recruitment of PTEN at the postsynaptic membrane leads to excessive removal of AMPA receptors, skewing synaptic plasticity towards depression and producing chronic synaptic weakening. (B) In some forms of autism, PTEN loss of function produces excessive neuronal proliferation and synaptic connectivity during development. In addition, these synapses will fail to be appropriately depressed during plasticity events because of insufficient (or lack of) PTEN activity. This will result in synaptic hyperactivity, which will eventually exacerbate the hyperconnectivity and hyperexcitability phenotypes that started during brain development.

Our New Nature Neuroscience Paper:

PTEN gates Alzheimer's pathogenesis 

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.











 Our New book on Cognitive Enhancement:

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.