Cited by 224Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsNeurogenesis and neuroplasticity mechanisms

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

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Lee, Sarah Emerson, Simons, Stephen B., Heldt, Scott A., Zhao, Meilan, Schroeder, Jason P., Vellano, Christopher P., Cowan, D. Patrick, Ramineni, Suneela +8 more·2010·Proceedings of the National Academy of Sciences

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.

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Crossref · 10.1073/pnas.1005362107

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Authors
Lee, S. E., Simons, S. B., Heldt, S. A., Zhao, M., Schroeder, J. P., Vellano, C. P., Cowan, D. P., Ramineni, S., Yates, C. K., Feng, Y., Smith, Y., Sweatt, J. D., Weinshenker, D., Ressler, K. J., Dudek, S. M., & Hepler, J. R.
Affiliations
  • Departments of aPharmacology,
  • National Institutes of Health (US)
  • Psychiatry and Behavioral Sciences, and
  • Human Genetics,
  • Emory University (US)
  • University of Alabama (US)
  • Emory National Primate Research Center (US)
Corresponding author
  • Lee, Sarah Emerson
  • Vellano, Christopher P.
  • Cowan, D. Patrick
  • Ramineni, Suneela
  • Yates, Cindee K.
  • Feng, Yue
  • Hepler, John R.
Venue
Proceedings of the National Academy of Sciences
Published
2010-09-13
Volume
107
Issue
39
Pages
16994-16998
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2039668561
Cited by
224
References
49
Citations by year
2026: 10 · 2025: 14 · 2024: 17 · 2023: 28 · 2022: 12 · 2021: 20 · 2020: 18 · 2019: 14 · 2018: 23 · 2017: 6 · 2016: 12 · 2015: 10 · 2014: 10 · 2013: 7 · 2012: 11
FWCI
3.87
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Burroughs Wellcome Fund (DA019624)
  • Emory University (RR00165)
  • National Institutes of Health (RR‐00165, NS037112, NS57098, NS055077)
  • National Institute on Drug Abuse (R01DA019624, R01DA017963)
  • National Institute of General Medical Sciences (T32GM008602)
  • National Institute of Neurological Disorders and Stroke (P30 NS57098, P30NS055077, R01NS049195, P30NS057098, R01NS037112)
  • National Institute of Environmental Health Sciences (Z01ES100221, ZIAES100221)
  • National Center for Research Resources (RR-00 165, P51RR000165)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
RGS14, hippocampal CA2, synaptic plasticity, long-term potentiation, Schaffer collateral synapses, ERK MAP kinase signaling, G protein signaling, spatial learning, object recognition memory
MeSH terms
Animals, Learning, Memory, Neuronal Plasticity, Synapses, Pyramidal Cells, Mice, Knockout, RGS Proteins, Mice, CA2 Region, Hippocampal

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