The interactive nature of cannabis and schizophrenia risk genes

Cannabis increases the risk of developing schizophrenia in genetically vulnerable individuals. Genetically modified mice offer a means to improve our understanding of the genes that confer vulnerability to the effects of cannabis in humans. Such models have been useful in forward (mouse to human) and reverse (human to mouse) translational research. On one hand, mouse research guides human studies on which genes to focus on; on the other hand, human studies that identify genetic variants can then be modeled in mice in an effort to delineate mechanisms involved in gene–cannabis interactions. This chapter will focus on two genes that are associated with schizophrenia, and appear to confer vulnerability to the effects of cannabis on psychosis—that is, the genes for catechol-O-methyltransferase (COMT) and neuregulin 1 (NRG1). Importantly, both genes have been investigated in mouse and human studies. COMT–cannabis interactions were first identified in human schizophrenia studies that were then reverse translated to mice, in order to appraise basic mechanisms. NRG1–cannabis interactions were first identified in mouse studies, as mice hypomorphic for transmembrane domain Nrg1 displayed altered neurobehavioral responses to cannabinoids in schizophrenia-relevant domains. The Nrg1-cannabis interaction was then confirmed in human studies. This chapter will focus on mouse preclinical research, which has improved our understanding how COMT and Nrg1 modulate the schizophrenia-relevant effects of cannabinoids.