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

• Published in: eLife 2019-08, Vol.8
• Main Authors: Huang, Yung-Chi, Pirri, Jennifer K, Rayes, Diego, Gao, Shangbang, Mulcahy, Ben, Grant, Jeff, Saheki, Yasunori, Francis, Michael M, Zhen, Mei, Alkema, Mark J
• Format: Article
• Language: English
• Subjects: acetylcholine; Animals; behavior; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; calcium; Calcium - metabolism; GABA; Gain of Function Mutation; Genetics and Genomics; ion channel; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mutant Proteins - genetics; Mutant Proteins - metabolism; Neuroscience; neurotransmission; Synaptic Transmission
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.45905

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.