Brain, Vol. 123, No. 3, 463-471,
March 2000
© 2000 Oxford University Press
Invited review |
Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering 
1A Ca2+ channel mutation
1 Departments of Physiology, 2 Neurology and 3 Human Genetics, Leiden University Medical Centre, Leiden,The Netherlands
Correspondence to:
Dr P.C. Molenaar, Department of Physiology, Leiden University Medical Centre, Wassenaarseweg 62, PO Box 9604, 2300 RC Leiden, The Netherlands E-mail: p.c.molenaar{at}physiology.medfac.leidenuniv.nl
Neurotransmitter release at many synapses is regulated by P/Q-type Ca2+ channels containing the 
1A pore-forming subunit. Mutations in 1A cause cerebral disorders including familial hemiplegic migraine (FHM) and ataxia in humans. Tottering (tg) 1A mutant mice display ataxia and epilepsy. It is not known whether 1A mutations induce impairment of synaptic function, which could underlie the symptoms of these cerebral disorders. To assess whether 1A mutations influence neurotransmitter release, we studied P-type Ca2+ channel-mediated acetylcholine (ACh) release at tg neuromuscular junctions (NMJs) with micro-electrode measurements of synaptic potentials. We found a Ca2+-, Mg2+- and K+-dependent increase of spontaneous ACh release at both homo- and heterozygote tg NMJs. Furthermore, there was increased run-down of high-rate evoked release at homozygous tg NMJs. In isotonic contraction experiments this led to block of synaptic transmission at lower concentrations of the ACh antagonist tubocurarine than were needed in wild-type muscles. Our results suggest that in tg motor nerve terminals there is increased influx of Ca2+ under resting conditions. This study shows that functional consequences of 1A mutations causing cerebral disorders can be characterized at the NMJ.
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