CACNA1C Modulation of Mood Disorder Pathophysiology in the Mesolimbic Dopamine System

Abstract

Title: CACNA1C Modulation of Mood Disorder Pathophysiology in the Mesolimbic Dopamine System By: Chantelle E. Terrillion, Doctor of Philosophy, 2015 Dissertation Directed by: Todd Gould, Associate Professor, Department of Psychiatry Neuropsychiatric mood disorders, including bipolar disorder and major depression, are a severe and prevalent public health concern. Bipolar disorder and major depression are common in the population, and result in overwhelming costs to individuals. Despite the high prevalence and debilitating characteristics of these disorders, little is known about the biological mechanisms underlying them, and the result is limited effective treatment options. There is a strong genetic component to bipolar disorder and major depression, and Genome Wide Association Studies (GWAS) have identified several genetic risk factors, including CACNA1C, which codes for the ?1C subunit of the L-type calcium channel (LTCC) Cav1.2. Studies in human patients and controls have associated single nucleotide polymorphisms (SNPs) in CACNA1C with changes in brain structure and function, as well as higher scores on depression rating scales. Dysregulation of the mesolimbic dopamine (ML-DA) system has been linked to these disorders, and LTCCs are associated with normal function of the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway. Despite mounting evidence that Cacna1c is important in the etiology of mood disorders, it is unclear how variations of CACNA1C levels may modify risk. I proposed that Cav1.2 channels mediate ML-DA system function, leading to changes in a subset of dopamine-mediated behaviors relevant to mood disorders. I investigated the role of Cav1.2 channel function on a subset of stimulant mediated behaviors and dopaminergic neurotransmission in the ML-DA system, as well as investigated the role of Cacna1c within the NAc in mediating the behavioral effects of social stress. I found that genetically and pharmacologically decreased Cav1.2 channel function was associated with attenuation of selective dopamine dependent behaviors, and fast-scan cyclic voltammetry revealed a role for Cacna1c in presynaptic ML-DA signaling. Furthermore, I found that Cacna1c in the NAc mediates susceptibility to social defeat. Overall, my data indicates that Cacna1c in the VTA-NAc pathway mediates behaviors relevant to both bipolar mania and bipolar depression. With an increased understanding of the function of Cacna1c in the ML-DA system advances knowledge of the biological mechanisms underlying a genetic susceptibility factor for mood disorders, potentially leading to improved prevention and treatment of disease.