Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering alpha(1A) Ca2+ channel mutation

Neurotransmitter release at many synapses is regulated by P/Q-type Ca2+ cha nnels containing the alpha(1A) pore-forming subunit. Mutations in alpha(1A) cause cerebral disorders including familial hemiplegic migraine (FHM) and ataxia in humans. Tottering (tg) alpha(1A) mutant mice display ataxia and e pilepsy. It is not known whether alii mutations induce impairment of synapt ic function, which could underlie the symptoms of these cerebral disorders. To assess whether alpha(1A) mutations influence neurotransmitter release, we studied P-type Ca2+ channel-mediated acetylcholine (ACh) release at tg n euromuscular junctions (NMJs) with micro-electrode measurements of synaptic potentials. We found a Ca2+-, Mg2+- and K+-dependent increase of spontaneo us ACh release at both homo- and heterozygote tg NMJs, Furthermore, there w as increased run-down of high-rate evoked release at homozygous tg NMJs, In isotonic contraction experiments this led to block of synaptic transmissio n at lower concentrations of the ACh antagonist tubocurarine than were need ed in wild-type muscles. Our results suggest that in tg motor nerve termina ls there is increased influx of Ca2+ under resting conditions. This study s hows that functional consequences of alpha(1A) mutations causing cerebral d isorders can be characterized at the NMJ.