Cacna1c haploinsufficiency lacks effects on adult hippocampal neurogenesis and volumetric properties of prefrontal cortex and hippocampus in female rats

Physiol Behav. 2020 Sep 1;223:112974. doi: 10.1016/j.physbeh.2020.112974. Epub 2020 May 28.

Abstract

The cross-disorder risk gene CACNA1C is strongly involved in the etiology of all major neuropsychiatric disorders, with women often being more affected by CACNA1C mutations than men. Human neuroimaging studies provided evidence that CACNA1C variants are associated with anatomical and functional brain alterations, such as decreased prefrontal volumes, microstructural changes in the hippocampus, and reduced hippocampal activity during memory tasks. In mouse models, Cacna1c alterations were repeatedly linked to disorder-like behavioral phenotypes and reduced adult hippocampal neurogenesis, which has been implicated in the pathology of neuropsychiatric disorders. Here, we applied a recently developed rat model and conducted two studies to investigate the effects of partial Cacna1c depletion on adult hippocampal neurogenesis and volumetric properties of the hippocampus and the prefrontal cortex in adult female constitutive heterozygous (Cacna1c+/-) rats and wildtype (Cacna1c+/+) littermate controls. In study 1, we analyzed proliferation versus survival of adult-born hippocampal cells based on a 5-bromodeoxyuridine assay ensuring neuronal cell-type specificity through applying an immunofluorescent multiple staining approach. In study 2, we performed a detailed volumetric analysis with high structural resolution of the dorsal hippocampus and the medial prefrontal cortex, including their major substructures. Our results indicate comparable levels of cell proliferation and neuronal survival in Cacna1c+/- rats and Cacna1c+/+ controls. Additionally, we found similar volumes of the dorsal hippocampus and the medial prefrontal cortex across major substructures irrespective of genotype, indicating that Cacna1c haploinsufficiency has no prominent effects on these brain features in female rats.

Keywords: Adult hippocampal neurogenesis; Calcium; Cav1.2; Hippocampus; Medial prefrontal cortex; Neuropsychiatric disorders.