Characterization of acetylcholine release and the compensatory contribution of non-Cav2.1 channels at motor nerve terminals of leaner Cav2.1-mutant mice

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 Cav2.1 α1 protein. Cav2.1 is a neuronal Ca2+ 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 (Cav2.1-KO) mice, which display a neurological phenotype remarkably similar to that of Ln mice. However, using selective Cav channel blocking compounds we revealed a compensatory contribution profile of non-Cav2.1 type channels at Ln NMJs that differs completely from that at Cav2.1-KO NMJs. Our data indicate that the residual function and presence of Ln-mutated Cav2.1 channels precludes presynaptic compensatory recruitment of Cav1 and Cav2.2 channels, and hampers that of Cav2.3 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.