Gerald OBERMAIR

α₂δ mutations linked to brain disorders affect synaptic functions

α₂δ proteins serve as auxiliary subunits of voltage-gated calcium channels, which are essential components of excitable cells such as nerve and muscle cells. Over the recent years, α₂δ proteins have been identified as critical regulators of synaptic functions. Moreover, the genes encoding for the four α₂δ isoforms have been linked to neurological and neurodevelopmental disorders including epilepsy, autism spectrum disorders, schizophrenia, and depressive and bipolar disorders. Despite the increasing number of potentially disease-associated mutations, the underlying pathophysiological mechanisms are only beginning to emerge. Using heterologous and homologous expression and analyses of specific knockout and mutant mouse models, we show that mutated α₂δ proteins can alter synaptic functions, both, via their role as calcium channel subunits and as independent regulatory entities.