Activation of Metabotropic Glutamate Receptor 3 Modulates Thalamo-accumbal Transmission and Rescues Schizophrenia-like Physiological and Behavioral Deficits.

BACKGROUND: Polymorphisms in the gene encoding for metabotropic glutamate receptor 3 (mGlu3) are associated with an increased likelihood of schizophrenia diagnosis and can predict improvements in negative symptoms following treatment with antipsychotics. However, the mechanisms by which mGlu3 can regulate brain circuits involved in schizophrenia pathophysiology are not clear. METHODS: We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, slice optogenetics, and fiber photometry to investigate the effects of mGlu3 activation on phencyclidine (PCP)-induced impairments in thalamo-accumbal transmission and sociability deficits. A chemogenetic approach was used to evaluate the role of thalamo-accumbal transmission in PCP-induced sociability deficits. RESULTS: We first established that PCP treatment augmented excitatory transmission onto dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc) and induced sociability deficits. Our studies revealed a selective increase in glutamatergic synaptic transmission from thalamic afferents to D1-MSNs in the NAc shell. Chemogenetic silencing of thalamo-accumbal inputs rescued PCP-induced sociability deficits. Pharmacological activation of mGlu3 normalized PCP-induced impairments in thalamo-accumbal transmission and sociability deficits. Mechanistic studies revealed that mGlu3 activation induced robust long-term depression at synapses from the thalamic projections onto D1-MSNs in the NAc shell. CONCLUSIONS: These data demonstrate that activation of mGlu3 decreases thalamo-accumbal transmission and thereby rescues sociability deficits in mouse modeling schizophrenia-like symptoms. These findings provide novel insights into the NAc-specific mechanisms and suggest that agents modulating glutamatergic signaling in the NAc may provide a promising approach for treating negative symptoms in schizophrenia.

Metabotropic glutamate receptor 3 as a potential therapeutic target for psychiatric and neurological disorders.

Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As metabotropic glutamate receptor 3 (mGlu3 receptor) regulates glutamatergic transmission in various brain areas, emerging literature suggests that targeting mGlu3 receptors can be a novel approach to the treatment of psychiatric and neurological disorders. For example, mGlu3 receptor negative allosteric modulators (NAMs) induce rapid antidepressant-like effects in both acute and chronic stress models. Activation of mGlu3 receptors can enhance cognition in the rodents modeling schizophrenia-like pathophysiology. The mGlu3 receptors expressed in the astrocytes induce neuroprotective effects. Although polymorphisms in GRM3 have been shown to be associated with addiction, there is not significant evidence about the efficacy of mGlu3 receptor ligands in rodent models of addiction. Collectively, drugs targeting mGlu3 receptors may provide an alternative approach to fill the unmet clinical need for safer and more efficacious therapeutics for CNS disorders.