# Nucleus Accumbens Proteome Disbalance in an Adolescent Mouse Model of Schizophrenia and Nicotine Misuse Comorbidity

## TL;DR

This study explores how the nucleus accumbens proteome is disrupted in a mouse model of schizophrenia and nicotine misuse, revealing shared and sex-specific pathways.

## Contribution

The study identifies Ncam1 as a potential marker for synaptic plasticity disbalance and reveals sex-specific proteomic changes in a comorbidity model.

## Key findings

- Cytoskeleton, synaptic plasticity, energy metabolism, and nervous system development pathways were affected in both sexes.
- Ncam1 was deregulated in the nucleus accumbens of both male and female mice, suggesting a central role in the comorbidity.
- Cs and Mapk3 were exclusively deregulated in female and male mice, respectively, indicating sex-specific effects.

## Abstract

Background/Objectives: Schizophrenia and nicotine misuse are a comorbid condition that frequently develops during adolescence. Considering the role of the nucleus accumbens (NAcc) as a common neurobiological substrate for these psychiatric disorders, label-free proteomics was employed to identify NAcc deregulated proteins in male and female mouse models of schizophrenia with a history of adolescent nicotine exposure. Methods: Phencyclidine was used to model schizophrenia, and minipump infusions were used to model nicotine misuse. Results: Enrichment Reactome pathway and protein–protein interaction analyses showed that the cytoskeleton and associated synaptic plasticity mechanisms, energy metabolism, and nervous system development were affected in both sexes. In particular, Ncam1 (Neural cell adhesion molecule 1) could be of interest as a candidate marker of synaptic plasticity disbalance. Its deregulation in the NAcc of both sexes suggests that it lies at the core of the comorbidity pathophysiology. When considering sex-selective effects, Cs (Citrate synthase) and Mapk3 (Mitogen-activated protein kinase 3) were identified as exclusively deregulated in female and male mice, respectively. Since both proteins were previously shown to be exclusively deregulated in the medial prefrontal cortex of co-modeled mice, a common mesocortical and mesolimbic system effect can be inferred, supporting the role of aberrant energy metabolism and synaptic plasticity in the comorbidity model. Conclusions: The current data provide insights into the NAcc proteome disbalance in an adolescent preclinical model of combined schizophrenia and nicotine misuse, pointing to relevant pathways and early markers of the comorbidity.