Papers of the Week

Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of mutants. mutants display increased cholinergic- and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.