info:eu-repo/semantics/article
Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans
Fecha
2019-08-05Registro en:
Huang, Yung Chi; Pirri, Jennifer K.; Rayes, Diego Hernán; Gao, Shangbang; Mulcahy, Ben; et al.; Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans; eLife Sciences Publications Ltd; eLife; 8; 05-8-2019; 1-28
2050-084X
CONICET Digital
CONICET
Autor
Huang, Yung Chi
Pirri, Jennifer K.
Rayes, Diego Hernán
Gao, Shangbang
Mulcahy, Ben
Grant, Jeff
Saheki, Yasunori
Francis, Michael M.
Zhen, Mei
Alkema, Mark J.
Resumen
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.