Surprisingly, the reduction in evoked release was accompanied by an ∼ 3-fold increase in spontaneous ACh release. Compared to wild-type, RN NMJs had 50–75% lower nerve stimulation-evoked transmitter release, explaining the observed muscle weakness. In ex vivo electrophysiological experiments we found severely impaired ACh release. Muscle contraction experiments showed a compromised safety factor of neuromuscular transmission. Clinical muscle weakness and fatigue were demonstrated using repetitive nerve-stimulation electromyography, grip strength testing and an inverted grid hanging test.

We tested neuromuscular function of RN mice and characterized transmitter release properties at their NMJs in diaphragm, soleus and flexor digitorum brevis muscles. The dysfunction may resemble the situation in Lambert–Eaton myasthenic syndrome (LEMS), in which autoantibodies target Cav2.1 channels at NMJs, inducing severely reduced ACh release and resulting in muscle weakness. Therefore, Cav2.1 dysfunction induced by the RN mutation may disturb ACh release at the NMJ. Besides being the predominant type of Cav channel in the cerebellum, Cav2.1 channels mediate acetylcholine (ACh) release at the peripheral neuromuscular junction (NMJ). The ataxic mouse rolling Nagoya (RN) carries a missense mutation in the Cacna1a gene, encoding the pore-forming subunit of neuronal Cav2.1 (P/Q-type) Ca2+ channels.

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