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To whom correspondence should be addressed. E-mail: jhepler@pharm.emory.edu.

Edited by Lutz Birnbaumer, National Institute of Environmental Health Sciences, Research Triangle Park, NC, and approved August 17, 2010 (received for review April 19, 2010)

Author contributions: S.E.L., J.P.S., Y.F., Y.S., J.D.S., D.W., K.J.R., S.M.D., and J.R.H. designed research; S.E.L., S.B.S., S.A.H., M.Z., C.P.V., D.P.C., S.R., and C.K.Y. performed research; S.E.L., S.B.S., M.Z., S.A.H., and J.P.S. analyzed data; and S.E.L., S.M.D., and J.R.H. wrote the paper.

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Research Funding:

This work was supported by National Institutes of Health Grants R01 NS037112 and R01 NS049195 (to J.R.H.), Grant R01 DA017963 (to D.W.), Grant R01 DA019624 and the Burroughs Wellcome Fund (to K.J.R.), the Yerkes Primate Center Base Grant RR00165 (to Y.S.), Emory National Institute of Neurological Disorders and Stroke Neuroscience Core Facilities Grant P30 NS055077, Training Grant 5 T32 GM008602 to the Emory Molecular and Systems Pharmacology graduate program, and the National Institutes of Health Neuroscience Blueprint Core Grant P30 NS57098 (to J.D.S.). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES100221, to S.M.D.).

Keywords:

  • long-term potentiation
  • hippocampus
  • G protein signaling
  • RGS proteins
  • ERK

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory

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Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 107, Number 39

Publisher:

, Pages 16994-16998

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)–CA3–CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is area CA2, an intervening hippocampal region that is poorly understood. Schaffer collateral synapses on CA2 neurons are distinct from those on other hippocampal neurons in that they exhibit a perplexing lack of synaptic long-term potentiation (LTP). Here we demonstrate that the signaling protein RGS14 is highly enriched in CA2 pyramidal neurons and plays a role in suppression of both synaptic plasticity at these synapses and hippocampal-based learning and memory. RGS14 is a scaffolding protein that integrates G protein and H-Ras/ERK/MAP kinase signaling pathways, thereby making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, deletion of exons 2–7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) and now express robust LTP at glutamatergic synapses in CA2 neurons with no impact on synaptic plasticity in CA1 neurons. Treatment of RGS14-deficient CA2 neurons with a specific MEK inhibitor blocked this LTP, suggesting a role for ERK/MAP kinase signaling pathways in this process. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in spatial learning and in object recognition memory compared with their wild-type littermates, but showed no differences in their performance on tests of nonhippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory but distinct from the canonical DG–CA3–CA1 circuit.

Copyright information:

Beginning with articles submitted in Volume 106 (2009) the author(s) retains copyright to individual articles, and the National Academy of Sciences of the United States of America retains an exclusive license to publish these articles and holds copyright to the collective work.

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