Interaction of the Psychiatric Risk Gene Cacna1c With Post-weaning Social Isolation or Environmental Enrichment Does Not Affect Brain Mitochondrial Bioenergetics in Rats.

Susanne Michels,Rainer K W Schwarting,Moria D Braun,Carsten Culmsee,Marcella Rietschel,Markus Wöhr,Theresa M Kisko,Astrid Dempfle,Amalia M Dolga,Stephanie H Witt,A Özge Sungur

doi:10.3389/fncel.2019.00483

Abstract

The pathophysiology of neuropsychiatric disorders involves complex interactions between genetic and environmental risk factors. Confirmed by several genome-wide association studies, Cacna1c represents one of the most robustly replicated psychiatric risk genes. Besides genetic predispositions, environmental stress such as childhood maltreatment also contributes to enhanced disease vulnerability. Both, Cacna1c gene variants and stressful life events are associated with morphological alterations in the prefrontal cortex and the hippocampus. Emerging evidence suggests impaired mitochondrial bioenergetics as a possible underlying mechanism of these regional brain abnormalities. In the present study, we simulated the interaction of psychiatric disease-relevant genetic and environmental factors in rodents to investigate their potential effect on brain mitochondrial function using a constitutive heterozygous Cacna1c rat model in combination with a four-week exposure to either post-weaning social isolation, standard housing, or social and physical environmental enrichment. Mitochondria were isolated from the prefrontal cortex and the hippocampus to evaluate their bioenergetics, membrane potential, reactive oxygen species production, and respiratory chain complex protein levels. None of these parameters were considerably affected in this particular gene-environment setting. These negative results were very robust in all tested conditions demonstrating that Cacna1c depletion did not significantly translate into altered bioenergetic characteristics. Thus, further investigations are required to determine the disease-related effects on brain mitochondria.

Highlights

Neuropsychiatric disorders such as major depression, bipolar disorder, schizophrenia, and autism are highly prevalent, multifaceted, and heterogeneous diseases with shared symptomatic features (Adam, 2013)
In order to study the combined effects of a heterozygous Cacna1c knockout and different environmental influences on brain mitochondria, we first validated the reduction of CaV 1.2 levels in Cacna1c+/− rats, compared the mean body weight per group, examined the prefrontal cortex (PFC)/HC tissue weight, and verified the functional integrity of the isolated mitochondria
The same applies to the CaV 1.2 protein levels in the HC of Cacna1c+/− versus Cacna1c+/+ rats

Summary

Introduction

Neuropsychiatric disorders such as major depression, bipolar disorder, schizophrenia, and autism are highly prevalent, multifaceted, and heterogeneous diseases with shared symptomatic features (Adam, 2013). Identified by genome-wide association studies, Cacna1c represents the most robustly replicated psychiatric risk gene in major depression, bipolar disorder, schizophrenia, and autism. Cacna1c encodes the α1C subunit of the major L-type calcium channel (LTCC) in the brain (CaV 1.2) (Bhat et al, 2012; CrossDisorder Group of the Psychiatric Genomics Consortium, 2013). Several studies provide convincing evidence that the risk variant rs1006737 is associated with altered CaV 1.2 expression, impaired calcium signaling, as well as compromised structure and function of brain regions relevant for characteristic behavioral changes observed in psychiatric patients (Bhat et al, 2012; Erk et al, 2014; Paulus et al, 2014). Affected brain regions include the prefrontal cortex (PFC) and the hippocampus (HC), which are essential for stress regulation, emotion, cognition, learning, and memory (Busatto, 2013). Embryonic deletion of Cacna1c in mouse forebrain glutamatergic neurons results in diminished synaptic plasticity, cognitive decline, and reduced sociability (Dedic et al, 2018)

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Conclusion