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.