Mechanisms of mGluR-dependent plasticity in hippocampal area CA2

Pyramidal cells in hippocampal area CA2 have synaptic properties that are distinct from the other CA subregions. Notably, this includes a lack of typical long-term potentiation of stratum radiatum synapses. CA2 neurons express high levels of several known and potential regulators of metabotropic glutamate receptor (mGluR)-dependent signaling including Striatal-Enriched Tyrosine Phosphatase (STEP) and several Regulator of G-protein Signaling (RGS) proteins, yet the functions of these proteins in regulating mGluR-dependent synaptic plasticity in CA2 are completely unknown. Thus, the aim of this study was to examine mGluR-dependent synaptic depression and to determine whether STEP and the RGS proteins RGS4 and RGS14 are involved. Using whole cell voltage-clamp recordings from mouse pyramidal cells, we found that mGluR agonist-induced long-term depression (mGluR-LTD) is more pronounced in CA2 compared with that observed in CA1. This mGluR-LTD in CA2 was found to be protein synthesis and STEP dependent, suggesting that CA2 mGluR-LTD shares mechanistic processes with those seen in CA1, but in addition, RGS14, but not RGS4, was essential for mGluR-LTD in CA2. In addition, we found that exogenous application of STEP could rescue mGluR-LTD in RGS14 KO slices. Supporting a role for CA2 synaptic plasticity in social cognition, we found that RGS14 KO mice had impaired social recognition memory as assessed in a social discrimination task. These results highlight possible roles for mGluRs, RGS14, and STEP in CA2-dependent behaviors, perhaps by biasing the dominant form of synaptic plasticity away from LTP and toward LTD in CA2.

Automated summary

Pyramidal cells in hippocampal area CA2 have distinct synaptic properties, including a lack of typical long-term potentiation. This study investigated the role of metabotropic glutamate receptor (mGluR)-dependent signaling regulators in CA2 synaptic plasticity. The results showed that mGluR agonist-induced long-term depression (mGluR-LTD) is more pronounced in CA2 compared to CA1, and that this process depends on protein synthesis and the presence of STEP and RGS14 proteins. Additionally, RGS14 was found to play a crucial role in CA2 mGluR-LTD. Furthermore, RGS14 knockout mice showed impaired social recognition memory, suggesting a role for CA2 synaptic plasticity in social cognition.