GABA _B Receptors Gate Sex-Specific Synaptic Plasticity in the Nucleus Accumbens

Excitatory synaptic plasticity within the nucleus accumbens (NAc) drives motivated behaviors, and dysregulation is implicated in several psychiatric disorders marked by impaired reward processing. The NAc integrates glutamatergic input, which conveys information about reward, context, and behavioral goals, with local GABAergic signaling that regulates excitatory transmission and medium spiny neuron (MSNs) output. However, little is known regarding GABA-dependent modulation of activity-dependent excitatory synaptic plasticity. Here, we investigated GABA _B receptor (GABA _B R) regulation of plasticity at hippocampus (Hipp)-NAc synapses, at which plasticity is a key mediator of reward-related behaviors. Using whole-cell electrophysiological recordings in mouse brain slices, we found that pharmacological inhibition of GABA _B Rs converts long-term potentiation (LTP) into long-term depression (LTD) selectively in females, identifying a sex-specific role for GABA _B Rs in modulating long-term plasticity of Hipp-MSN synapses. This LTD required mGluR5 activation and estrogen receptor alpha (ERα) in both D1- and D2-expressing MSN subtypes, while only D1-MSNs suggested that LTD was expressed presynaptically through a CB1 receptor-dependent mechanism. Notably, GABA _B R inhibition did not alter basal synaptic transmission, indicating a specific role for these receptors in gating plasticity beyond regulation of basal excitatory drive. Together, these findings identify a novel, sex-specific mechanism by which GABA _B Rs control the direction of synaptic plasticity.