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

Shalini Dogra; Caleb Aguayo; Zixiu Xiang; Jason Putnam; Joshua Smith; Curran Johnston; Daniel J Foster; Craig W Lindsley; Colleen M Niswender; P Jeffrey Conn

doi:10.1016/j.biopsych.2023.11.023

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

Biol Psychiatry. 2023 Dec 5:S0006-3223(23)01753-5. doi: 10.1016/j.biopsych.2023.11.023. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee. Electronic address: shalini.dogra@vanderbilt.edu.
² Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee.
³ Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina.
⁴ Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt University, Nashville, Tennessee; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee.
⁵ Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee.
⁶ Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee. Electronic address: jeff.conn@vanderbilt.edu.

PMID: 38061467
DOI: 10.1016/j.biopsych.2023.11.023

Abstract

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.

Keywords: Negative symptoms; Nucleus accumbens; Schizophrenia; Synaptic plasticity; Thalamo-accumbal transmission; mGlu(3).

Abstract

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