Unraveling the cell type-specific effects and mechanisms of cross-disorder risk gene CACNA1C

Loganathan, Srivaishnavi (2022): Unraveling the cell type-specific effects and mechanisms of cross-disorder risk gene CACNA1C. Dissertation, LMU München: Fakultät für Biologie

Abstract

The cross-disorder risk gene CACNA1C, coding for the α1 subunit of the L-type voltage-gated calcium channel Cav1.2, has been repeatedly implicated in the etiology of psychiatric disorders. In humans, genetic variations in CACNA1C have a sex-dependent influence on the symptoms and age of onset of psychiatric disorders. In addition to genetic risk factors, environmental factors such as stress add considerably to the risk of development of psychiatric disorders. However, the underlying mechanisms which manifest the disease symptoms are not clearly understood. Rodent models of Cav1.2 have revealed behavioral phenotypes reminiscent of core symptoms of psychiatric disorders but are largely biased toward male animals. In addition, the role of Cav1.2 channels in inhibitory neurons remains yet to be investigated. Thus, the aim of this study was to dissect Cav1.2-specific circuits and downstream signaling mechanisms to fundamentally increase our understanding of the role L-type calcium channels play in the pathogenesis of psychiatric disorders. To reach this goal, a series of behavioral, cellular, and molecular experiments were performed to investigate: 1) gene × environment interactions in animals with a specific deletion of Cav1.2 channels in excitatory neurons (Cav1.2-Nex) upon exposure to early life stress, 2) changes in disease-related endophenotypes and the effects of estrous cycle in female Cav1.2-Nex mice, 3) alterations in disease-related phenotypes caused by cell type-specific Cav1.2 channel deletion in parvalbumin-expressing inhibitory neurons and 4) alterations in Cav1.2 downstream signaling pathways, structural plasticity, and their functional implications. The major findings of this study include: LBN stress induced only moderate effects on behavioral phenotypes of male and female Cav1.2-Nex mice and dendritic atrophy was observed in stressed mice. Female Cav1.2-Nex conditional knockout animals exhibited hyperactivity, anxiety-related behavior, cognitive deficits, active stress coping behavior, and structural impairments in the hippocampus. In addition, an enhanced baseline activity was observed in primary cortical neurons derived from Cav1.2-Nex knockout animals. Cav1.2-PV conditional knockout animals exhibited anxiety-related behavior, cognitive deficit, passive stress coping behavior and differential cFos expression in several brain regions.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: CACNA1C, Cav1.2, L-type calcium channel, parvalbumin neurons, sex-dependent influences
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 19. Dezember 2022
• 1. Bericht­erstatter:in: Schmidt, Mathias