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

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.

Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration

“…Of note, another small molecule inhibitor against the dynamin family member dynamin-related protein 1 (Drp1), mdivi-1, was shown to block mitochondrial complex I-dependent oxygen consumption, and reverse electron transfer-mediated ROS production [ 27 ]. Therefore, in order to test whether dynasore may similarly directly affect complex I activity or mitochondrial respiration in general, we tested the effect of dynasore on the respiratory capacity of isolated mitochondria in cell-free systems, as was done previously [ 20 ]. However, in these cell-free systems, dynasore did not directly affect mitochondrial respiration ( Figure 3 I).…”

“…Mitochondria were isolated from the prefrontal cortex of Sprague Dawley rat brains, as described in Michels et al [ 20 ]. Eight micrograms of purified mitochondria were used per well.…”

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

“…Transgenic rodent models demonstrate some behavioral defects that parallel humans with CACNA1C SNPs (Bhat et al, 2012;Kabir et al, 2016). With respect to "autism-like" behaviors, CACNA1C heterozygous mice show mild defects in social behavior but very few changes in exploratory, anxiety-like, and learning behaviors (Kabitzke et al, 2018) while CACNA1C haploinsufficient rats do display mild defects in prosocial vocalizations without other overt behavioral phenotypes and even mild improvements in spatial memory function (Braun et al, 2018;Kisko et al, 2018;Michels et al, 2019). Haploinsufficient CACNA1C mice demonstrated reduced anxiety, reduced locomotion in the amphetamine-induced hyperactivity model of psychosis, and reduced depressive-like behavioral phenotypes (Dao et al, 2010).…”

The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation

“…As described previously 16 , 17 , in vitro experiments were performed using 2–4-month-old female C57BL/6 mice (Jackson Laboratory, Bar Harbor, Maine). In vivo experiments were performed using 4-month-old female C57BL/6 mice, weighing 20.7 g ± 1.3 g (Jackson Laboratory, Bar Harbor, ME, USA).…”

“…As described previously 16 , 17 , animals were anesthetized via intraperitoneal (i.p.) injections of ketamine (100 mg/kg) and xylazine (10 mg/kg).…”