Abstract
The severely ataxic and epileptic mouse leaner ( Ln) carries a natural splice site mutation in Cacna1a, leading to a C-terminal truncation of the encoded Ca v2.1 α 1 protein. Ca v2.1 is a neuronal Ca 2+ channel, mediating neurotransmitter release at many central synapses and the peripheral neuromuscular junction (NMJ). With electrophysiological analyses we demonstrate severely reduced (∼50%) neurotransmitter release at Ln NMJs. This equals the reduction at NMJs of Cacna1a null-mutant (Ca v2.1-KO) mice, which display a neurological phenotype remarkably similar to that of Ln mice. However, using selective Ca v channel blocking compounds we revealed a compensatory contribution profile of non-Ca v2.1 type channels at Ln NMJs that differs completely from that at Ca v2.1-KO NMJs. Our data indicate that the residual function and presence of Ln-mutated Ca v2.1 channels precludes presynaptic compensatory recruitment of Ca v1 and Ca v2.2 channels, and hampers that of Ca v2.3 channels. This is the first report directly showing at single synapses the deficits and plasticity in transmitter release resulting from the Ln mutation of Cacna1a.
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