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Downregulation of the psychiatric susceptibility gene Cacna1c promotes mitochondrial resilience to oxidative stress in neuronal cells.

ABSTRACT: Affective disorders such as major depression and bipolar disorder are among the most prevalent forms of mental illness and their etiologies involve complex interactions between genetic and environmental risk factors. Over the past ten years, several genome wide association studies (GWAS) have identified CACNA1C as one of the strongest genetic risk factors for the development of affective disorders. However, its role in disease pathogenesis is still largely unknown. Vulnerability to affective disorders also involves diverse environmental risk factors such as perinatal insults, childhood maltreatment, and other adverse pathophysiological or psychosocial life events. At the cellular level, such environmental influences may activate oxidative stress pathways, thereby altering neuronal plasticity and function. Mitochondria are the key organelles of energy metabolism and, further, highly important for the adaptation to oxidative stress. Accordingly, multiple lines of evidence including post-mortem brain and neuro-imaging studies suggest that psychiatric disorders are accompanied by mitochondrial dysfunction. In this study, we investigated the effects of Cacna1c downregulation in combination with glutamate-induced oxidative stress on mitochondrial function, Ca2+ homeostasis, and cell viability in mouse hippocampal HT22 cells. We found that the siRNA-mediated knockdown of Cacna1c preserved mitochondrial morphology, mitochondrial membrane potential, and ATP levels after glutamate treatment. Further, Cacna1c silencing inhibited excessive mitochondrial reactive oxygen species formation and calcium influx, and protected the HT22 cells from oxidative cell death. Overall, our findings suggest that the GWAS-confirmed psychiatric risk gene CACNA1C plays a major role in oxidative stress pathways with particular impact on mitochondrial integrity and function.

SUBMITTER: Michels S

PROVIDER: S-EPMC5945680 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Downregulation of the psychiatric susceptibility gene <i>Cacna1c</i> promotes mitochondrial resilience to oxidative stress in neuronal cells.

Michels Susanne S Ganjam Goutham K GK Martins Helena H Schratt Gerhard M GM Wöhr Markus M Schwarting Rainer K W RKW Culmsee Carsten C

Cell death discovery 20180510

Affective disorders such as major depression and bipolar disorder are among the most prevalent forms of mental illness and their etiologies involve complex interactions between genetic and environmental risk factors. Over the past ten years, several genome wide association studies (GWAS) have identified <i>CACNA1C</i> as one of the strongest genetic risk factors for the development of affective disorders. However, its role in disease pathogenesis is still largely unknown. Vulnerability to affect ...[more]

PMID: 29760952

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Project description:BackgroundStress and stressful life events have repeatedly been shown as causally related to depression. The Chronic Mild Stress rat model is a valid model of stress-induced depression. Like humans, rats display great heterogeneity in their response to stress and adversity. Hence some individuals are stress-sensitive and prone to develop depression-like behaviour in response to modest stressors, while others are stress-resilient and remain essentially symptom free.ObjectivesCompared to the large body of research, which describes stress-induced maladaptive neurobiological changes, relatively little attention has been devoted to understand resiliency to stress. The aim of the present study was to identify changes in neuronal activity, associated with stress-resilient and stress-susceptible chronic mild stress endophenotypes, by examining c-Fos expression in 13 different brain areas. Changes in c-Fos expression have been reported as associated to stressful conditions.MethodsStress-induced modulation of neuronal activation patterns in response to the chronic mild stress paradigm was mapped using the immediate early gene expression c-Fos as a marker. Quantification of the c-Fos-like immunoreactivity responses was done by semi-automated profile counting procedures and design-based stereology.ResultsExposure to chronic mild stress significantly altered c-Fos expression in a total of 6 out of 13 investigated areas. Chronic mild stress was found to suppress the c-Fos response within the magnocellular ventral lateral geniculate nucleus of both stress subgroups. In the the lateral and ventral orbital cortices of stress-resilient rats, the c-Fos like immunoreactivity response was also repressed by stress exposure. On the contrary the c-Fos response within the amygdala, medial habenula, and infralimbic cortex was increased selectively for the stress-susceptible rats.ConclusionsThe study was initiated to characterize neuronal substrates associated with stress-coping mechanisms. Six areas, all of which represents limbic structures, were found to be sensitive to stress exposure. The effects within these areas associate to the hedonic status of the rats. Hence, these areas might be associated to stress-coping mechanisms underlying the chronic mild stress induced segregation into stress-susceptible and stress-resilient endophenotypes.

Dataset Information

Downregulation of the psychiatric susceptibility gene Cacna1c promotes mitochondrial resilience to oxidative stress in neuronal cells.

Publications

Downregulation of the psychiatric susceptibility gene <i>Cacna1c</i> promotes mitochondrial resilience to oxidative stress in neuronal cells.

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