Stable expression of voltage-gated calcium channel mRNA in αδ (CACNA2D) knockout mouse brains.

Voltage-gated Ca channels (VGCCs) regulate Ca entry in healthy and diseased neurons, and their function is modulated by auxiliary αδ subunits. Among the four αδ isoforms, αδ-1, αδ-2, and αδ-3 show overlapping expression in various brain regions, raising questions about their respective specific and redundant roles. Here, we investigated if the loss of αδ isoforms affects mRNA expression of other VGCC α, αδ, and β subunits. Moreover, qPCR expression profiling in knockout conditions provides insights into potential compensatory mechanisms. To this end, we analyzed the expression of the high-VGCC complement, including seven α, four β, and four αδ subunit isoforms, in hippocampal and striatal tissues from αδ single and αδ-1/-3 double knockout mice. Our findings reveal that mRNA expression profiles of hippocampal and striatal tissues contain the entire set of neuronal high-VGCC subunits. Notably, αδ-3 mRNA is the most abundant isoform in striatum and αδ-1/-3 double knockout mice show increased amounts of mutant αδ-3 mRNA reporter transcripts compared to αδ-3 single knockout mice. These findings support a critical role of αδ-3 in GABAergic striatal medium spiny neurons. Of note, mRNA expression levels of individual α and β isoforms were remarkably similar between αδ single knockout and αδ-1/-3 double knockout compared to control mice. Taken together, our study provides novel insights into the resilience of VGCC mRNA levels to disruptions of αδ isoform expression, suggesting transcriptional stability of core calcium channel components comparable to housekeeping genes. However, this stability does not fully prevent physiological deficits, suggesting limited functional compensation at the transcript level.