Abstract
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.
Highlights
Maintenance of proper brain function requires the balance of excitatory and inhibitory synaptic transmission
Unc-2/CaV2α(gf) differentially affects excitatory and inhibitory synapses How does an increase of UNC-2/CaV2α activity lead to an E/I imbalance? Since changes in neuronal activity can modulate synaptic protein distribution (Frank, 2014; Turrigiano, 2012), we examined the morphology of pre- and post-synaptic markers at cholinergic and GABAergic neuromuscular junction (NMJ) (Fig. 6)
The negative shift in the activation potential of UNC-2/CaV2α(GF) channel is reminiscent of similar observations for several mutant human CaV2.1α channels that have been identified in patients with familial hemiplegic migraine type 1 (FHM1) (Hans et al, 1999; Tottene et al, 2005; Müllner et al, 2004)
Summary
Instituto de Investigaciones Bioquímicas de Bahía Blanca (CONICET), Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca, Argentina. 3 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada Department of Molecular Genetics, Department of Physiology, Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada 4 Present address: College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China 5 Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior, The Rockefeller University, New York, NY 10065, USA Present address: Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore
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