Auxiliary α₂δ subunits of voltage-gated calcium channels modulate channel trafficking, current properties, and synapse formation. Three of the four isoforms (α₂δ-1, α₂δ-2, and α₂δ-3) are abundantly expressed in the brain; however, of the available knockout models, only α₂δ-2 knockout or mutant mice display an obvious abnormal neurological phenotype. Thus, we hypothesize that the neuronal α₂δ isoforms may have partially specific as well as redundant functions. To address this, we generated three distinct α₂δ double knockout mouse models by crossbreeding single knockout (α₂δ-1 and -3) or mutant (α₂δ-2/ducky) mice. Here, we provide a first phenotypic description and brain structure analysis. We found that genotypic distribution of neonatal litters in distinct α₂δ-1/-2, α₂δ-1/-3, and α₂δ-2/-3 breeding combinations did not conform to Mendel’s law, suggesting premature lethality of single and double knockout mice. Notably, high occurrences of infant mortality correlated with the absence of specific α₂δ isoforms (α₂Δ-2 > α₂δ-1 > α₂δ-3), and was particularly observed in cages with behaviorally abnormal parenting animals of α₂δ-2/-3 cross-breedings. Juvenile α₂δ-1/-2 and α₂δ-2/-3 double knockout mice displayed a waddling gate similar to ducky mice. However, in contrast to ducky and α₂δ-1/-3 double knockout animals, α₂δ-1/-2 and α₂δ-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 α₂δ subunits differentially regulate premature survival, postnatal growth, brain development, and behavior, suggesting specific neuronal functions in health and disease.