The integral role of PTEN in brain function: from neurogenesis to synaptic plasticity and social behavior.

Abstract

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene is a critical tumor suppressor that plays an essential role in the development and functionality of the central nervous system. Located on chromosome 10 in humans and chromosome 19 in mice, PTEN encodes a protein that regulates cellular processes such as division, proliferation, growth, and survival by antagonizing the PI3K‑Akt‑mTOR signaling pathway. In neurons, PTEN dephosphorylates phosphatidylinositol‑3,4,5‑trisphosphate (PIP3) to PIP2, thereby modulating key signaling cascades involved in neurogenesis, neuronal migration, and synaptic plasticity. PTEN is crucial for embryonic neurogenesis, controlling the proliferation of neural progenitor cells and guiding the migration and proper lamination of neurons in cortical and hippocampal structures. It also regulates dendritic growth and axon guidance, ensuring correct neuronal connectivity. In postnatal neurogenesis, PTEN maintains the balance of stem cell proliferation and integration of new neurons into existing circuits, particularly in the hippocampal dentate gyrus. Animal models with PTEN deletion or mutation exhibit significant structural and functional neuronal abnormalities, including enlarged soma and dendritic hypertrophy, increased synaptic density, and altered synaptic plasticity mechanisms such as long‑term potentiation and long‑term depression. These changes lead to deficits in learning and memory tasks, as well as impairments in social behaviors. PTEN mutations are associated with neurodevelopmental disorders like intellectual disability, epilepsy, and autism spectrum disorders accompanied by macrocephaly. Understanding PTEN's mechanisms offers valuable insights into its contributions to neurodevelopmental disorders and presents potential therapeutic targets for cognitive impairments and neurodegenerative diseases. Future research should focus on elucidating PTEN's functions in mature neurons and its influence on established neuronal networks, which may have significant implications for memory enhancement and behavioral modifications.