Disrupted-In-Schizophrenia-1 Gln31Leu Polymorphism Results in Social Anhedonia Associated with Monoaminergic Imbalance and Reduction of CREB and β-arrestin-1,2 in the Nucleus Accumbens in a Mouse Model of Depression

Abstract

Disrupted-in-schizophrenia-1 (DISC1) is associated with mental disorders, including major depression. We previously showed that DISC1-Q31L mutant mice have depression-like behaviors and can therefore be used to study neurobiological mechanisms of depression and antidepressant (AD) medication action. First, we found reduced levels of dopamine, serotonin and norepinephrine in the nucleus accumbens (NAC) of DISC1-Q31L mutants. Next, we assessed social-conditioned place preference as a reward-dependent task and the capacity of distinct ADs to correct impaired social behavior in DISC1-Q31L mice. Bupropion, but not fluoxetine or desipramine, was able to correct deficient social facilitation, social reward, and social novelty in DISC1-Q31L mutants, whereas all three ADs were able to improve social motivation and behavioral despair in DISC1-Q31L mutants. Furthermore, we sought to correlate social anhedonia with molecular and cellular features including dendritic spine density, β-arrestin-1,2, and cAMP-response-element-binding protein (CREB) in the NAC as biomarkers related to depression and the DISC1 pathway. DISC1-Q31L mutants showed reduced levels of β-arrestin-1,2, CREB, and spine density in the NAC, further supporting the construct validity of the genetic model. Bupropion induced the greatest effect on CREB in DISC1-Q31L mutants, whereas all studied ADs corrected the reduced levels of β-arrestin-1,2 and modestly ameliorated deficient spine density in this brain region. Overall, we find neurobiological changes accompanying social anhedonia in the NAC of DISC1-Q31L mutant mice, consistent with a role for DISC1 in regulating social reward as an endophenotype of depression.

Oxytocin in the regulation of social behaviours in medial amygdala‐lesioned mice via the inhibition of the extracellular signal‐regulated kinase signalling pathway

“…Previous studies have shown that CREB and c‐fos are downstream proteins of the ERK signalling pathway . Cyclic adenosine monophosphate response element‐binding has been shown to be associated with learning and memory . Consistent with previous reports, the results of the present study indicated that OXT reduced ERK phosphorylation and downregulated the expression of CREB and c‐fos.…”

Role of basal ganglia neurocircuitry in the pathology of psychiatric disorders

“…Similarly, deficits in social interaction, working memory, and executive function have been reported in some DISC1 mutant strains . Several strains of DISC1 mutant mice also demonstrate altered dopamine function in the striatum, with increased levels of dopamine D2 receptors and dopamine transporter, and decreased basal levels of dopamine . These studies indicate DISC1 mice to be a useful animal model for investigating schizophrenia‐associated symptoms, and suggest DISC1 as a potential therapeutic target for psychiatric conditions, including schizophrenia …”

Olanzapine-induced DNA methylation in the hippocampus and cerebellum in genes mapped to human 22q11 and implicated in schizophrenia

“…Specifically, they are involved in proline and L-DOPA degradation, cell-cell signaling and interaction, and nervous system development and function. Also, the affected genes have been implicated in psychosis including schizophrenia and bipolar disorder (Allen et al, 2008;Nyegaard et al, 2010;Lipina et al, 2013), excessive anxiety induced by stress (Bignante et al, 2008), and depressive-like behavior (Zhu et al, 2012). In addition to the association of Prodh with schizophrenia, the gene was also implicated in the neurobiology of visual processing (Magnée et al, 2011).…”