Stable expression of voltage-gated calcium channel mRNA in α2δ (CACNA2D) knockout mouse brains

Voltage-gated Ca2+ channels (VGCCs) regulate Ca2+ entry in healthy and diseased neurons, and their function is modulated by auxiliary α2δ subunits. Among the four α2δ isoforms, α2δ-1, α2δ-2, and α2δ-3 show overlapping expression in various brain regions, raising questions about their respective specific and redundant roles. Here, we investigated if the loss of α2δ isoforms affects mRNA expression of other VGCC α1, α2δ, 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 α1, four β, and four α2δ subunit isoforms, in hippocampal and striatal tissues from α2δ single and α2δ-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, α2δ-3 mRNA is the most abundant isoform in striatum and α2δ-1/-3 double knockout mice show increased amounts of mutant α2δ-3 mRNA reporter transcripts compared to α2δ-3 single knockout mice. These findings support a critical role of α2δ-3 in GABAergic striatal medium spiny neurons. Of note, mRNA expression levels of individual α1 and β isoforms were remarkably similar between α2δ single knockout and α2δ-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 α2δ 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.