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

Abstract

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 postmortem 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.

Finding associations in a heterogeneous setting: Statistical test for aberration enrichment

“…Several of these genes have been implicated with schizophrenia in the literature. For example, LIN7A is at the overlap of several rare CNVs associated with schizophrenia in [12] and induced overexpression of CNRIP1 is known to cause a schizophrenia like-phenotype in mice [48]. NMNAT2 is important for the maintenance of neurons and is known to be neuroprotective in several models of neurological disorders [2], while HLA-DRB1 is the most frequently reported genetic association to Schizophrenia [70].…”

Orexin Modulation of VTA Dopamine Neuron Activity: Relevance to Schizophrenia

“…Thus, we used the MAM rodent model, which displays neurophysiological and behavioral deficits consistent with schizophrenia to examine whether targeting the ORX system could reverse the mesolimbic dopamine system dysfunction, commonly observed in individuals with schizophrenia. As mentioned previously, numerous rodent models used to study the neurobiology of schizophrenia exhibit a significant increase in dopamine neuron population activity ( Lodge and Grace, 2007 ; Shah and Lodge, 2013 ; Aguilar, 2014 ; Boley et al, 2014 ; Perez et al, 2016 , 2019a , 2019b ). We observed a similar increase in MAM-treated vehicle rats, as they displayed a significant increase in VTA dopamine neuron population activity compared with saline-treated vehicle rats.…”

Cannabinoid Receptor Interacting Protein 1a (CRIP1a): Function and Structure

“…CRIP1a has been linked to neuropathological states such as epilepsy and neurotoxicity in the hippocampus [11,12,13,14], schizophrenia phenotype [15,16], and motor dysfunction and addiction in the striatum [17], making the CRIP1a-CB 1 receptor interaction an accessible target for novel drug design. This review focused on the structural interaction between the CB 1 receptor and its association with CRIP1a.…”

“…The purpose of the present review is to describe the unique interactions that CRIP1a can have with the CB 1 receptor to regulate cellular signaling and CB 1 receptor trafficking. Regulation of CB 1 receptor activity by CRIP1a can be investigated at both the functional and structural levels with the goal of designing peptide or small molecule drugs that can selectively target the CRIP1a-CB 1 receptor interaction for therapeutic intervention in the treatment of pain, convulsions [11,12,13,14], schizophrenia [15,16], and neurodegenerative motor disorders [17].…”