Department of Neurobiology; Alkema Lab; Francis Lab
Genetic Phenomena | Genetics and Genomics | Nervous System | Neuroscience and Neurobiology
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 alpha1 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, genetics, genomics, neuroscience
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© 2019, Huang et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
DOI of Published Version
Elife. 2019 Aug 5;8. pii: e45905. doi: 10.7554/eLife.45905. Link to article on publisher's site
Huang, Yung-Chi; Pirri, Jennifer K.; Rayes, Diego; Gao, Shangbang; Mulcahy, Ben; Grant, Jeff; Saheki, Yasunori; Francis, Michael M.; Zhen, Mei; and Alkema, Mark J., "Gain-of-function mutations in the UNC-2/CaV2alpha channel lead to excitation-dominant synaptic transmission in C. elegans" (2019). Neurobiology Publications and Presentations. 243.
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