PI3Kγ is required for NMDA receptor-dependent long-term depression and behavioral flexibility

Nat Neurosci. 2011 Oct 23;14(11):1447-54. doi: 10.1038/nn.2937.

Abstract

Phosphatidylinositol 3-kinase (PI3K) has been implicated in synaptic plasticity and other neural functions in the brain. However, the role of individual PI3K isoforms in the brain is unclear. We investigated the role of PI3Kγ in hippocampal-dependent synaptic plasticity and cognitive functions. We found that PI3Kγ has a crucial and specific role in NMDA receptor (NMDAR)-mediated synaptic plasticity at mouse Schaffer collateral-commissural synapses. Both genetic deletion and pharmacological inhibition of PI3Kγ disrupted NMDAR long-term depression (LTD) while leaving other forms of synaptic plasticity intact. Accompanying this physiological deficit, the impairment of NMDAR LTD by PI3Kγ blockade was specifically correlated with deficits in behavioral flexibility. These findings suggest that a specific PI3K isoform, PI3Kγ, is critical for NMDAR LTD and some forms of cognitive function. Thus, individual isoforms of PI3Ks may have distinct roles in different types of synaptic plasticity and may therefore influence various kinds of behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Biophysics
  • Chromones / pharmacology
  • Class Ib Phosphatidylinositol 3-Kinase / deficiency
  • Class Ib Phosphatidylinositol 3-Kinase / metabolism*
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology
  • Electric Stimulation / methods
  • Environment
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agents / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Extinction, Psychological / physiology
  • Fear / physiology
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / cytology
  • In Vitro Techniques
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / genetics*
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morpholines / pharmacology
  • Neurons / drug effects
  • Neurons / physiology*
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / metabolism
  • Phosphorylation / genetics
  • Quinoxalines / pharmacology
  • RNA, Messenger / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Thiazolidinediones / pharmacology
  • Time Factors

Substances

  • 5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
  • Chromones
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agents
  • Morpholines
  • Quinoxalines
  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • Thiazolidinediones
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Methoxyhydroxyphenylglycol
  • Class Ib Phosphatidylinositol 3-Kinase
  • Pik3cg protein, mouse
  • Glycogen Synthase Kinase 3 beta
  • Oncogene Protein v-akt
  • Glycogen Synthase Kinase 3
  • 3,4-dihydroxyphenylglycol