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.
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.