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Elife. 2019 Aug 5;8. pii: e45905. doi: 10.7554/eLife.45905.

Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in Caenorhabditis elegans.

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Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior, The Rockefeller University, New York, United States.
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Department of Physiology, University of Toronto, Toronto, Canada.


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 Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic and decreased GABAergic transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) 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.


C. elegans; GABA; acetylcholine; behavior; calcium; genetics; genomics; ion channel; neuroscience; neurotransmission

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