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RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory
Open accessAbstract
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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“We confirmed that the Cre+ cells were indeed CA2 PNs by demonstrating co-staining for RGS1412 (97.38 ± 0.31% overlap; n = 4 mice, 2546 cells”
From The hippocampal CA2 region is essential for social memory (2014) · cites this paper as [12]
In the citing paper
“This effect is dependent upon the ERK/MAPK pathways, given that facilitated LTP in the CA2 was blocked by U0126, a MEK inhibitor”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Lee et al., 2010
In the citing paper
“The RGS14 gene knockout mouse exhibited improved NOP memory and facilitation of LTP in the CA2, but not CA1, area.”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Lee et al., 2010
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Metadata
- 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.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-09-13
- Volume
- 107
- Issue
- 39
- Pages
- 16994-16998
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2947872
- 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
- bronze
- doi.org
- 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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