Rasd2 is a striatal GTP-binding protein that modulates Akt and mTOR signaling cascades, well known to be highly vulnerable pathways in psychiatric disorders.

We investigated the association of Rasd2 and its genetic variation with a series of prefronto-striatal phenotypes related to psychosis in rodents and humans.

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.

Rasd2 knockout mice were employed to evaluate schizophrenia-like behaviors induced by psychotomimetic drugs like amphetamine and phencyclidine. Furthermore, we investigated if RASD2genetic 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 RASD2mRNA expression levels in post-mortem brains of patients with schizophrenia and bipolar disorder.

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.

Collectively, our data suggests that RASD2represents a gene of potential interest in psychiatric disorders for its ability to modulate prefronto-striatal phenotypes related to schizophrenia.

D-aspartate (D-Asp) is an atypical amino acid that binds to and activates NMDARs. D-Asp occurs abundantly in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-Aspartate Oxidase (DDO). The agonistic activity of D-Asp on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for NMDAR-related alterations observed in schizophrenia. Consistently, substantial reduction of D-Asp was observed in post-mortem schizophrenia brains.

We evaluated the potential contribution of D-Asp as neurodevelopmental modulator of brain circuits and behaviors relevant to schizophrenia.

We analyzed DDO mRNA expression in the post-mortem prefrontal cortex of schizophrenic patients. Moreover, we treated knockout mice for Ddo gene (Ddo-/-) with the NMDAR antagonist phencyclidine to evaluate their schizophrenia-relevant behaviors and circuits. Finally, we assessed cortico-hippocampal connectivity of these mice.

DDO mRNA detection was performed by quantitative PCR. Phencyclidine-induced schizophrenia-like behaviours were assessed through motor activity and prepulse inhibition paradigms. Resting-state and pharmacological fMRI were used to evaluate functional circuits and connectivity.

DDO mRNA expression is increased in frontal samples of schizophrenic patients. In mice, the absence of Ddo gene produces a significant reduction in phencyclidine-induced motor hyper-activity and prepulse inhibition deficit. Furthermore, increased levels of D-Asp in Ddo-/- animals significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia.

Our data suggest that D-Asp, through the regulation exerted by DDO, may have a role in the pathophysiology of schizophrenia.