Rasd2 Modulates Psychotomimetic Drug Effects in Mice and Schizophrenia-related Phenotypes in Humans

Abstract

Background Rasd2 is a striatal GTP-binding protein that modulates Akt and mTOR signaling cascades, well known to be highly vulnerable pathways in psychiatric disorders. Aims We investigated the association of Rasd2 and its genetic variation with a series of prefronto-striatal phenotypes related to psychosis in rodents and humans. Objectives We want to provide evidence that Rasd2 controls the vulnerability to schizophrenia-related behavior induced by psychothomimetic drugs in mice. Moreover, we aim to find genetic variations within the Rasd2 gene that influence a series of brain schizophrenia-related phenotypes in human. Methods Rasd2 knockout mice were employed to evaluate schizophrenia-like behaviors induced by psychotomimetic drugs like amphetamine and phencyclidine. Furthermore, we investigated if RASD2 genetic variations in humans are associated with mRNA expression in post-mortem prefrontal cortex, as well as prefrontal and striatal grey matter volume and physiology during working memory as measured with MRI in healthy subjects. Finally, we assessed RASD2 mRNA expression levels in post-mortem brains of patients with schizophrenia and bipolar disorder. Results We found that both psychotomimetics triggered greater vulnerability to motor stimulation and to prepulse inhibition deficits in Rasd2 mutants. In humans, we found that a genetic variation (rs6518956) within RASD2 predicts prefrontal mRNA expression as well as prefrontal grey matter volume and prefronto-striatal activity during working memory. Finally, we reported that RASD2 mRNA expression is slightly reduced in post-mortem prefrontal cortex of patients with schizophrenia. Conclusions Collectively, our data suggests that RASD2 represents a gene of potential interest in psychiatric disorders for its ability to modulate prefronto-striatal phenotypes related to schizophrenia.