Abstract
Disrupted-in-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and affective disorders. The full-length DISC1 protein consists of an N-terminal ‘head’ domain and a C-terminal tail domain that contains several predicted coiled-coils, structural motifs involved in protein-protein interactions. To probe the in vivo effects of missense mutation of DISC1’s C-terminal tail, we tested mice carrying mutation D453G within a predicted α-helical coiled-coil region. We report that, relative to wild-type littermates, female DISC1D453G mice exhibited novelty-induced hyperlocomotion, an anxiogenic profile in the elevated plus-maze and open field tests, and reduced social exploration of unfamiliar mice. Male DISC1D453G mice displayed a deficit in passive avoidance, while neither males nor females exhibited any impairment in startle reactivity or prepulse inhibition. Whole brain homogenates showed normal levels of DISC1 protein, but decreased binding of DISC1 to GSK3β, decreased phospho-inhibition of GSK3β at serine 9, and decreased levels of β-catenin in DISC1D453G mice of either sex. Interrupted GSK3β signaling may thus be part of the mechanism underlying the behavioral phenotype associated with D453G, in common with the previously described N-terminal domain mutations Q31L and L100P in mice, and the schizophrenia risk-conferring variant R264Q in humans.
Highlights
IntroductionSchizophrenia is a severe psychiatric condition characterized by three clusters of symptoms: positive symptoms (psychosis and thought disorder), negative symptoms (social and emotional deficits), and cognitive symptoms[1,2]
Schizophrenia is a severe psychiatric condition characterized by three clusters of symptoms: positive symptoms, negative symptoms, and cognitive symptoms[1,2]
Based on all three programs predicting D453G to affect Disrupted-in-Schizophrenia 1 (DISC1) protein function, we bred homozygous mutant and wild-type littermates for assessment in a series of behavioral tests to evaluate the effects of D453G on different domains of the mouse behavioral repertoire
Summary
Schizophrenia is a severe psychiatric condition characterized by three clusters of symptoms: positive symptoms (psychosis and thought disorder), negative symptoms (social and emotional deficits), and cognitive symptoms[1,2]. It is well established from family, twin and adoption studies that genetic factors play an important role in the risk of developing schizophrenia[3]. Two ethylnitrosourea (ENU)-derived mutant Disc[1] mouse lines have previously been described, each with a different missense mutation in the N-terminal head domain of DISC1: Q31L and L100P24 Both mutants have inhibited cortical neuronal proliferation, aberrant neuronal migration, reduced dendritic spine density[25], reduced brain volumes and deficits in spatial working memory[24] compared with wild-type mice. The Q31L mice exhibit a more depressive-like behavior, with abnormalities in social behavior and the forced swim test, partially ameliorated by the antidepressant bupropion, but not by rolipram, a PDE4 inhibitor[24]
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