Activation of group II metabotropic glutamate (mGlu2/3) receptors regulates excitatory synaptic plasticity in the nucleus accumbens: Implications for the treatment of schizophrenia

Abstract

Accumulating clinical evidence suggests that glutamatergic dysfunction may contribute to the pathogenesis of schizophrenia. Several studies have shown beneficial effects of group II metabotropic glutamate (mGlu2/3) receptor agonists in rodents modeling schizophrenia symptomatology. However, the mechanisms through which mGlu2/3 receptor agonists modulate glutamatergic neurotransmission in the nucleus accumbens (NAc) and schizophrenia‐like symptoms are still not clear. Therefore, we performed a series of experiments to evaluate the role of mGlu2/3 receptors in regulating glutamatergic neurotransmission in the NAc. Using ex vivo whole‐cell patch‐clamp electrophysiology, we showed that bath application of mGlu2/3 receptor agonist, LY379268 (100 nM), induces long‐term depression (LTD) of excitatory neurotransmission onto D1 medium spiny neurons (MSNs) in the NAc. Further, we evaluated the expression of mGlu2/3‐LTD over the glutamatergic inputs from the midline nuclei of the thalamus (mThal) and basolateral amygdala (BLA) to the NAc. Interestingly, group II mGlu receptor agonist, LY379268, induces LTD of mThal‐NAc projections, but not BLA‐NAc projections, to D1 MSNs. Further, to test the hypothesis that mGlu2/3 receptor activation can normalize glutamatergic neurotransmission in the NAc of mouse models of schizophrenia, we first measured spontaneous excitatory postsynaptic currents (sEPSCs) onto D1 MSNs of NAc in the slices prepared from the mice treated with either saline or MK801 (0.2 mg/kg; s.c., 30 minutes). We found that acute treatment with MK801 enhances the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) onto D1 MSNs. Subsequently, we examined the effect of group II agonist on MK801‐induced dysregulation of excitatory neurotransmission in the NAc. Excitingly, bath application of group II agonist, LY379268 (100 nM), reversed the MK801‐induced changes in sEPSCs in the NAc. Collectively, these data provide an evidence that activation of mGlu2/3 receptors can rescue schizophrenia‐like pathophysiology in the NAc.