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

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.

Keywords: E-cigarette; co-exposure; mass spectrometry; mental disorder; mesolimbic system; nicotine addiction; prodrome; proteome.

Figure 1

Venn diagrams (top panels) showing deregulated proteins in the NAcc of female (left) and male (right) mouse models of SCHZ (PCP), nicotine misuse (NIC), or the comorbidity (PCPNIC) when compared to controls (CT). Volcano plots (lower panels) provide a general picture of fold change magnitude (x-axis) and p-values (y-axis) of the dataset. Blue dots indicate downregulated proteins, red dots indicate upregulated ones, gray dots indicate proteins that did not reach deregulation criteria (>1.5 fold change and p < 0.05). Candidate markers of the comorbidity are identified and will be discussed below.

Figure 2

Data from exclusively deregulated proteins in the NAcc of female and male mouse models of the comorbidity (PCPNIC) when compared to controls (CT). The panels show top 10 Reactome pathways. Pathways in bold and underlined were shared between sexes. ▼ indicates that a given protein is downregulated in PCPNIC mice when compared to CT ones, while ▲ indicates that a given protein is upregulated. In the interaction networks, circles represent gene names, lines represent the interaction between proteins, and the results within the circle represent the structure of proteins. The proteins were analyzed by STRING, and the network was built using ‘medium confidence’ (0.4) interaction score. Each node represents a protein, and the line thickness indicates the strength of data support.

Figure 3

Data from proteins commonly deregulated in the NAcc of female and male mouse models of nicotine misuse (NIC) and the comorbidity (PCPNIC), when compared to controls (CT). The panels show top 10 Reactome pathways.▼indicates that a given protein is downregulated in NIC and PCPNIC mice when compared to CT ones, while ▲ indicates that a given protein is upregulated. In the interaction network, circles represent gene names, lines represent the interaction between proteins, and the results within the circle represent the structure of proteins. The proteins were analyzed by STRING, and the network was built using ‘medium confidence’ (0.4) interaction score. Each node represents a protein, and the line thickness indicates the strength of data support.

Figure 4

Data from proteins commonly deregulated in the NAcc of female and male mouse models of schizophrenia (PCP) and the comorbidity (PCPNIC), when compared to controls (CT). The panels show top 10 Reactome pathways.▼indicates that a given protein is downregulated in PCP and PCPNIC mice when compared to CT ones, while ▲ indicates that a given protein is upregulated. In the interaction network, circles represent gene names, lines represent the interaction between proteins, and the results within the circle represent the structure of proteins. The proteins were analyzed by STRING, and the network was built using ‘medium confidence’ (0.4) interaction score. Each node represents a protein, and the line thickness indicates the strength of data support.

Figure 5

Data from proteins commonly deregulated in the NAcc of female mouse models of schizophrenia (PCP), nicotine misuse (NIC), and the comorbidity (PCPNIC), when compared to controls (CT). The panel shows top 10 Reactome pathways.▼indicates that a given protein is downregulated in NIC, PCP, and PCPNIC mice when compared to CT ones, while ▲ indicates that a given protein is upregulated. In the interaction network, circles represent gene names, lines represent the interaction between proteins, and the results within the circle represent the structure of proteins. The proteins were analyzed by STRING, and the network was built using ‘medium confidence’ (0.4) interaction score. Each node represents a protein, and the line thickness indicates the strength of data support.