Expression of Alpha 1C Sub-Unit in Circadian Mouse Model for Bipolar

Education Level

Undergraduate

Faculty Advisor(s)

Professor Victoria Heimer-McGinn

Academic Department(s)

Psychology

Comments

This research was presented at the 2024 Rhode Island Summer Undergraduate Research Symposium, held on Friday, July 26, at the University of Rhode Island and supported by RI-INBRE.

Symposium Date

2024

Abstract

Bipolar disorder (BD) is a highly heritable chronic mood disorder characterized by manic episodes with cognitive deficits being an undertreated trait of the disease. These deficits are the best predicters of disease outcome and have begun to be studied in the CLOCKΔ19 mouse model which has good face and predictive validity for BD. In recent studies we have begun to show that the ClockΔ19 mouse model may serve as a valid model for translational study of the cognitive deficits reported by the clinical literature surrounding BD. In this study we seek to continue that research and elucidate the possible underlying molecular mechanisms of the deficits we observe. Several lines of evidence suggest that calcium (Ca2+) signaling is significantly associated with BD. The CACNA1C gene encodes for the alpha 1C subunit of L-type voltage gated calcium channels (VGCC) which is responsible for neuronal excitability. The strongest evidence for the association between Ca2+ signaling and BD is abnormalities in intracellular Ca2+ signaling found in platelets of BD patients. Supporting evidence from genome wide association studies (GWAS) also show a gain of function mutation in allele rs1006737 of CACNA1C gene being significantly associated with BD. This risk allele increases expression of CACNA1C in some areas of the brain leading to increased neuronal excitability exhibited by BD patients. In the current study we use a cohort of ClockΔ19 mice from our previous cognitive studies to examine the relative expression of CACNA1C in the prefrontal cortex (PFC) and hippocampus (HIPP) of (n=5) wild type, (n=3) heterozygous, and (n=3) homozygous ClockΔ19 mice. We expect that homozygous ClockΔ19 mice which have BD phenotypic traits will show increased expression of CACNA1C in the areas of the brain associated with cognitive the cognitive deficits seen in these mice. Furthermore, we expect that heterozygous ClockΔ19 will show increased CANA1C expression in these regions compared to wild types to a lesser extent then the homozygous mice as they are a translational representation of unaffected first degree relative of patients with BD. The results of the qPCR are currently being examined and might show a causative mechanism of the deficits previously seen in this mouse model of BD.

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