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

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.

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Figure 1: Synaptic and intrinsic properties of CA1 neurons in wild-type and Pik3cg−/− mice.
Figure 2: NMDAR LTD is absent in Pik3cg−/− mice.
Figure 3: NMDAR LTD is blocked by pharmacological inhibition of PI3Kγ.
Figure 4: Specificity of PI3Kγ in the induction of NMDAR LTD.
Figure 5: Recovery of NMDAR LTD impairment in Pik3cg−/− mice.
Figure 6: Signaling mechanisms involved in PI3Kγ-mediated NMDAR LTD.
Figure 7: Behavioral flexibility is reduced in Pik3cg−/− mice.

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Acknowledgements

This work was supported by the Creative Research Initiatives Program of the Korean Ministry of Science and Technology and World Class University project. J.-I.K. and H.-R.L. are supported by a BK21 fellowship and Seoul Science fellowship. S.-E.S. and J.B. are supported by a BK21 fellowship. P.H.B. is a Career Investigator of the Heart and Stroke Foundation of Ontario and has support from a Canadian Institutes of Health Research grant (62954). B.-K.K. is a Yonam Foundation Scholar. G.L.C. and M.Z. are WCU International Scholars.

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J.-I.K. and H.-R.L. designed, performed and analyzed most of the electrophysiology and behavioral experiments, and wrote the manuscript. S.S., J.B., N.-K.Y., J.-H.C., H.-G.K., Y.-S.L., S.-W.P., C.K., S.-J.A., S.Y.C., H.K., K.-H.K., D.-J.J., K.L. and S.J.K. conducted the biochemical, electrophysiological and behavioral studies. Y.-S.L., P.H.B., C.A.B., D.-J.J., K.L., E.K., M.Z. and G.L.C. aided in the interpretation of data and contributed to editing the manuscript. B.-K.K. supervised the project, designed the experiments and wrote the manuscript.

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Correspondence to Bong-Kiun Kaang.

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Kim, JI., Lee, HR., Sim, Se. et al. PI3Kγ is required for NMDA receptor–dependent long-term depression and behavioral flexibility. Nat Neurosci 14, 1447–1454 (2011). https://doi.org/10.1038/nn.2937

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