Abstract The pharmacological treatment of negative symptoms in schizophrenia remains a major unmet need. Among these, impairments in social functioning – manifesting as reduced adaptability and social withdrawal – are particularly disabling, as they persist beyond remission of positive symptoms and impede social reintegration. To investigate the neurobiological basis of behavioral impairments, we employed the tgDISC1 rat, a translational model overexpressing the human non-mutant Disrupted-in-Schizophrenia-1 (DISC1) gene. This overexpression results in DISC1 protein aggregation and aberrant signaling– molecular features identified in a subset of schizophrenia patients identified by elevated DISC1 aggregates in cerebrospinal fluid. Behaviorally, the tgDISC1 rats exhibited a selective loss of social novelty preference in the 3-Chamber task while maintaining intact social interest, indicating a specific deficit in social adaptability rather than social motivation. Here, we tested whether continuous administration of atypical antipsychotics amisulpride or clozapine would rescue social deficits in tgDISC1 rats. Treatment with amisulpride (0.2 and 0.8 mg/kg/day for two weeks) fully restored social novelty preference, whereas clozapine had no effect. Control tasks for anhedonia, short-term working memory, and explorative behavior confirmed that their phenotype was not secondary to global motivational or cognitive impairments. Together, these findings demonstrate that amisulpride, a selective D2/D3 receptor antagonist, rescues social adaptability deficits linked to aberrant DISC1 signaling. The results also highlight the success of our precision psychiatry approach: the biological definition of a subset of schizophrenia by identifying DISC1 protein aggregates, the generation of a corresponding animal model and a successful pharmacotherapy of a clinically relevant phenotype.
Dören et al. (2026) studied this question.