title: RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory.
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.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Sarah Emerson
authors.initials: SE
authors.lastname: Lee
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Simons
authors.forename: Scott A
authors.initials: SA
authors.lastname: Heldt
authors.forename: Meilan
authors.initials: M
authors.lastname: Zhao
authors.forename: Jason P
authors.initials: JP
authors.lastname: Schroeder
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Vellano
authors.forename: D Patrick
authors.initials: DP
authors.lastname: Cowan
authors.forename: Suneela
authors.initials: S
authors.lastname: Ramineni
authors.forename: Cindee K
authors.initials: CK
authors.lastname: Yates
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.forename: Serena M
authors.initials: SM
authors.lastname: Dudek
authors.forename: John R
authors.initials: JR
authors.lastname: Hepler
mesh_terms: D000818:Animals; D056651:CA2 Region, Hippocampal / Q000378:metabolism / Q000502:physiology*; D007858:Learning; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology*; D020710:RGS Proteins / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000502:physiology*
chemical_list: D020710:RGS Proteins; C491399:Rgs14 protein, mouse