REDUCED EXPRESSION OF METABOTROPIC GLYCINE RECEPTOR IN THE NUCLEUS ACCUMBENS CONTRIBUTES TO SYNAPTIC DYSFUNCTION IN STRESS-SUSCEPTIBLE MICE

We have recently identified metabotropic glycine receptor (mGlyR) as a key regulator of neuronal excitability in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) (PMID: 38884814). Given the strong implication of mGlyRs in stress-related disorders, we hypothesized that mGlyR signaling contributes to the synaptic neuroadaptations associated with stress resilience in mice. Using whole-cell patch-clamp recordings in acute NAc slices, we first investigated the synaptic effects of mGlyR activation. Glycine application selectively increased the amplitude of miniature excitatory postsynaptic currents (mEPSCs) without affecting their frequency or kinetics. mGlyR activation also enhanced evoked AMPAR-mediated EPSCs and increased the amplitude of long-term potentiation (LTP). These functional changes were paralleled by elevated phosphorylation of GluA1 at Ser831 and CREB at Ser133, as well as increased surface expression of GluA1. Interestingly, RNAscope analyses revealed a significant reduction in mGlyR mRNA expression in NAc MSNs from mice subjected to chronic unpredictable stress (CUMS) and displaying depressive-like behavior (susceptible), compared to resilient counterparts. Notably, stress-susceptible mice exhibited impaired mGlyR-dependent ability to enhance evoked AMPAR-mediated transmission and LTP. Together, these findings suggest that mGlyRs act as critical modulators of glutamatergic transmission and synaptic plasticity in the NAc. Moreover, our data indicate that reduced mGlyR signaling may contribute to stress susceptibility, positioning this receptor as a possible molecular determinant of stress resilience and a potential therapeutic target for stress-induced psychopathologies.