Gain-of-function mutations in the UNC-2/CaV2alpha channel lead to excitation-dominant synaptic transmission in C. elegans
Pirri, Jennifer K.
Francis, Michael M.
Alkema, Mark J
Student AuthorsJennifer K. (Pirri) Ingemi
Document TypeJournal Article
Genetics and Genomics
Neuroscience and Neurobiology
MetadataShow full item record
AbstractMutations 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.
Elife. 2019 Aug 5;8. pii: e45905. doi: 10.7554/eLife.45905. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/37970
Rights© 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.
Except where otherwise noted, this item's license is described as © 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.