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

Nature Neuroscience volume 14, pages 1447–1454 (2011)Cite this article

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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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  1. Jae-Ick Kim and Hye-Ryeon Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, National Creative Research Initiative Center for Memory, College of Natural Sciences, Seoul National University, Seoul, Korea

    Jae-Ick Kim, Hye-Ryeon Lee, Su-eon Sim, Jinhee Baek, Nam-Kyung Yu, Jun-Hyeok Choi, Hyoung-Gon Ko, Yong-Seok Lee, Soo-Won Park, Chuljung Kwak & Bong-Kiun Kaang

  2. Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea

    Su-eon Sim, Clarrisa A Bradley, Sang Jeong Kim, Min Zhuo, Graham L Collingridge & Bong-Kiun Kaang

  3. Department of Physiology, Seoul National University College of Medicine, Seoul, Korea

    Sung-Ji Ahn & Sang Jeong Kim

  4. Department of Anatomy, College of Medicine, Korea University, Seoul, Korea

    So Yoen Choi & Hyun Kim

  5. Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    Kyoung-Han Kim, Peter H Backx & Min Zhuo

  6. Department of Biological Sciences, National Creative Research Initiative Center for Synaptogenesis, Korea Advanced Institute of Science and Technology, Daejeon, Korea

    Eunjoon Kim

  7. Department of Applied Biology, College of Ecology and Environment, Kyungpook National University, Sangju-si, Kyeongbuk, Korea

    Deok-Jin Jang

  8. Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, Korea

    Kyungmin Lee

  9. MRC Center for Synaptic Plasticity, School of Physiology and Pharmacology, Bristol, UK

    Graham L Collingridge

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Contributions

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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