The Role of CHRM3 Overexpression in D1-MSNS in Promoting Anxiety- and Depressive-Like Behaviors

Abstract

Current therapeutic interventions for major depressive disorder (MDD) are notsufficiently effective, leaving more than 50% of patients symptomatic. To advance the development of new pharmaceutical treatments, novel molecular targets must be identified. The nucleus accumbens (NAc), a brain region that is key in the pathology of depression, contains a heterogenous neuron population that is predominantly D1- and D2- medium spiny neurons (MSNs). Previously, we have shown that the transcriptomic profiles of D1- and D2-MSNs are distinct, and that the D1 transcriptome correlates with susceptibility to depression. Further stress group specific transcriptome analysis showed that D1-MSNs within susceptible male mice have an overexpression of CHRM3, the gene encoding muscarinic acetylcholine receptor M3. To explore the effects of this differential gene expression in vivo, D1-Cre male mice were administered AAV-DIO-Chrm3 and AAVDIO- mCherry bilaterally to the NAc and were assessed for anxiety- and depressive-like behavior prior to and following submaximal stress exposure. Immunohistochemistry analysis showed that the cell-type specific viral overexpression of CHRM3 was successful. Behavioral measures of anxiety- and depressive-like behaviors revealed that though exposure to submaximal social stress was effective, increased susceptibility to social stress was not observed in animals with CHRM3 overexpression. These results indicate that an overexpression of CHRM3 within D1-MSNs is not sufficient to increase susceptibility to anxiety- and depressive-like behaviors. Future investigation of CHRM3 differential expression is required to elucidate its role in depression pathology.