FUNCTIONAL EXPRESSION OF GLUD1 RECEPTORS IN THE HIPPOCAMPAL CA2 FIELD

Fast synaptic neurotransmission relies primarily on ionotropic glutamate receptors (iGluRs) driving neuronal excitation and GABA_A receptors, driving inhibition. Our lab has recently made the unexpected observation that GluD1, an iGluR member, is not restricted to excitatory synapses but also present at inhibitory synapses in the hippocampus, where it binds GABA and modulates inhibitory synaptic plasticity at SLM-CA1 synapses (Piot et al., 2023). These findings challenge the established dichotomy between glutamatergic and GABAergic receptors, and raise new questions regarding GluD1 signaling mechanisms, synapse plasticity regulation and the control of excitation/inhibition balance in neuronal circuits. Although widely distributed in the adult mouse brain, GluD1 expression is predominant in several forebrain structures including neocortex, striatum, central amygdala and hippocampus (Hepp et al., 2015; Nakamoto et al., 2020). Here, we evaluate the expression and function of GluD1 in the CA2 hippocampal field, a structure with a particularly strong mRNA signal for GluD1. Immunohistochemistry confirms the prominent expression of GluD1 protein in CA2. Functional effects of GluD1 activation were assessed using patch-clamp experiments in acute brain slices from adult mice. In the presence of D-APV to prevent NMDAR activation, the application of the GluD1 agonist D-serine results in differential and reversible modulations of the various excitatory inputs into CA2 pyramidal neurons (CA3 Schaffer collaterals and perforant path from layer III of the entorhinal cortex), effects that were absent in slices from GluD1 knockout mice. Overall, these results suggest the presence of functional GluD1 receptors in the CA2 hippocampal field with potential for synapse-specific regulation.