title: Phosphatase and tensin homologue (PTEN) regulates synaptic plasticity independently of its effect on neuronal morphology and migration.
abstract: The tumour suppressor PTEN is the central negative regulator of the phosphatidylinositol 3-kinase (PI3K) signalling pathway, which mediates diverse processes in various tissues. In the nervous system, the PI3K pathway modulates proliferation, migration, cellular size, synaptic transmission and plasticity. In humans, neurological abnormalities such as autism, seizures and ataxia are associated with inherited PTEN mutations. In rodents, Pten loss during early development is associated with extensive deficits in neuronal migration and substantial hypertrophy of neurons and synaptic densities; however, whether its effect on synaptic transmission and plasticity is direct or mediated by structural abnormalities remains unknown. Here we analysed neuronal and synaptic structures and function in Pten-conditional knockout mice in which the gene was deleted from excitatory neurons postnatally. Using two-photon imaging, Golgi staining, immunohistochemistry, electron microscopy, and electrophysiological tools, we determined that Pten loss does not affect hippocampus development, neuronal or synaptic structures, or basal excitatory synaptic transmission. However, it does cause deficits in both major forms of synaptic plasticity, long-term potentiation and long-term depression, of excitatory synaptic transmission. These deficits coincided with impaired spatial memory, as measured in water maze tasks. Deletion of Pdk1, which encodes a positive downstream regulator of the PI3K pathway, rescued Pten-mediated deficits in synaptic plasticity but not in spatial memory. These results suggest that PTEN independently modulates functional and structural properties of hippocampal neurons and is directly involved in mechanisms of synaptic plasticity.
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Sperow
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Berry
authors.forename: Ildar T
authors.initials: IT
authors.lastname: Bayazitov
authors.forename: Guo
authors.initials: G
authors.lastname: Zhu
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Stanislav S
authors.initials: SS
authors.lastname: Zakharenko
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology; D002465:Cell Movement; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D017966:Pyramidal Cells / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse