Auxiliary alpha(2)delta subunits of voltage-gated calcium channels modulate channel trafficking, current properties, and synapse formation. Three of the four isoforms (alpha(2)delta-1, alpha(2)delta-2, and alpha(2)delta-3) are abundantly expressed in the brain; however, of the available knockout models, only alpha(2)delta-2 knockout or mutant mice display an obvious abnormal neurological phenotype. Thus, we hypothesize that the neuronal alpha(2)delta isoforms may have partially specific as well as redundant functions. To address this, we generated three distinct alpha(2)delta double knockout mouse models by crossbreeding single knockout (alpha(2)delta-1 and -3) or mutant (alpha(2)delta-2/ducky) mice. Here, we provide a first phenotypic description and brain structure analysis. We found that genotypic distribution of neonatal litters in distinct alpha(2)delta-1/-2, alpha(2)delta-1/-3, and alpha(2)delta-2/-3 breeding combinations did not conform to Mendelxxxs law, suggesting premature lethality of single and double knockout mice. Notably, high occurrences of infant mortality correlated with the absence of specific alpha(2)delta isoforms (alpha(2)Delta-2 > alpha(2)delta-1 > alpha(2)delta-3), and was particularly observed in cages with behaviorally abnormal parenting animals of alpha(2)delta-2/-3 cross-breedings. Juvenile alpha(2)delta-1/-2 and alpha(2)delta-2/-3 double knockout mice displayed a waddling gate similar to ducky mice. However, in contrast to ducky and alpha(2)delta-1/-3 double knockout animals, alpha(2)delta-1/-2 and alpha(2)delta-2/-3 double knockout mice showed a more severe disease progression and highly impaired development. The observed phenotypes within the individual mouse lines may be linked to differences in the volume of specific brain regions. Reduced cortical volume in ducky mice, for example, was associated with a progressively decreased space between neurons, suggesting a reduction of total synaptic connections. Taken together, our findings show that alpha(2)delta subunits differentially regulate premature survival, postnatal growth, brain development, and behavior, suggesting specific neuronal functions in health and disease.
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