Ventral hippocampal overexpression of Cannabinoid Receptor Interacting Protein 1 (CNRIP1)produces a schizophrenia-like phenotype in the rat

Adolescent cannabis use has been implicated as a risk factor for schizophrenia; however, it is neither necessary nor sufficient. Previous studies examining this association have focused primarily on the role of the cannabinoid receptor 1 (CB1R)with relatively little known about a key regulatory protein, the cannabinoid receptor interacting protein 1 (CNRIP1). CNRIP1 is an intracellular protein that interacts with the C-terminal tail of CB1R and regulates its intrinsic activity. Previous studies have demonstrated aberrant CNRIP1 DNA promoter methylation in post-mortem in human patients with schizophrenia, and we have recently reported decreased methylation of the CNRIP1 DNA promoter in the ventral hippocampus (vHipp)of a rodent model of schizophrenia susceptibility. To examine whether augmented CNRIP1 expression could contribute to the pathology of schizophrenia, we performed viral-mediated overexpression of CNRIP1 in the vHipp of Sprague Dawley rats. We then tested these rats for behavioral correlates of schizophrenia symptoms, followed by electrophysiology to determine the effects on the dopamine system, known to underlie psychosis. Here, we report that overexpression of vHipp CNRIP1 induces impairments in latent inhibition and social interaction, similar to those observed in individuals with schizophrenia and in rodent models of the disease. Furthermore, rats overexpressing vHipp CNRIP1 displayed a significant increase in ventral tegmental area (VTA)dopamine neuron population activity, a putative correlate of psychosis. These data provide evidence that alterations in CNRIP1 may contribute to the pathophysiology of schizophrenia, as overexpression is sufficient to produce neurophysiological and behavioral correlates consistently observed in rodent models of the disease.