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.long-term potentiation | hippocampus | G protein signaling | RGS proteins | ERK

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

“…C57Bl6/J background mice with systemic RGS14 gene deficiency were developed as previously described (Lee et al., 2010). RGS14 KO mice (RGS14tm1‐lex) were generated in the Transgenic Core Facility at Rutgers University—New Jersey Medical School, through the National Institutes of Health‐sponsored Mutant Mouse Regional Resource Center at http://www.informatics.jax.org/searches/accession_report.cgi?id=MGI:3528963.…”

“…RGS14 is a complex RGS family member that contains a canonical RGS domain, a tandem (R1 and R2) Ras/Rap binding domain (Kiel et al., 2005; Wohlgemuth et al., 2005), as well as a GoLoco/GPR motif. Most prior work on RGS14 focused on its effects on embryonic development and on the visual cortex and central nervous system (Evans, Lee, Smith & Hepler, 2014; Lee et al., 2010; Lopez‐Aranda et al., 2009; Shu, Ramineni & Hepler, 2010; Vellano, Brown, Blumer & Hepler, 2013). The role of BAT in RGS14 KO and its ability to enhance lifespan and improve metabolism, the focus of the present investigation, have never been explored.…”

Updating hippocampal representations: CA2 joins the circuit

“…The gene expression profile of neurons within CA2 (Box 2) is also increasingly well understood [48], and includes preferential expression of vasopressin 1b receptors [49] and strikingly selective expression of adenosine A1 receptors [50], fibroblast growth factor 2 (FGF-2) [51] and the Regulator of Gprotein Signaling 14 (RGS14) [52]. Combining these anatomical and proteomic signatures therefore enables objective identification of CA2's extent that can be used to target functional and physiological studies.…”

“…Unfortunately, the physiological impact of the mutation was not determined. Mutant mice lacking the CA2-enriched protein RGS14, which is involved in H-Ras/Mitogen-activated protein kinase (MAPK) signaling, demonstrated enhanced spatial learning and enhanced long-term potentiation (LTP) at the CA3-CA2 synapse [52].…”

Temporal control over the initiation of cell motility by a regulator of G-protein signaling

“…We provide evidence suggesting that Rgs14a exerts its function, at least in part, by regulating the level of E-cadherin on the cell membrane, thereby controlling the acquisition of cell motility. The link between Rgs14a and E-cadherin expression in this case could be relevant in other contexts such as the repression of synaptic plasticity in hippocampal neurons by Rgs14 (25), a phenomenon that is highly dependent on cell-cell adhesion as well (26). In the same direction, the role Rgs14 plays in determining the degree of interaction of migratory cells with cells in the environment where they are specified could be relevant in the case of dendritic cells and B lymphocytes.…”