Synaptic effects of mutations in neuronal Cav2.1 calcium channels

Abstract

Mutations in the CACNA1A gene, encoding neuronal Cav2.1 calcium channels, cause a wide spectrum of human neurological diseases, including familial hemiplegic migraine

type 1 (FHM1). The role of Cav2.1 channels is to mediate neurotransmitter release.

Using electrophysiological techniques, this thesis investigates the effects of several CACNA1A mutations on neurotransmitter release at the mouse neuromuscular junction (NMJ).

It is concluded that the FHM1 mutations R192Q and S218L increase neurotransmitter release and do not result in compensatory contributions of other types of calcium channels. Furthermore, it is shown that spontaneous neurotransmitter at the mouse NMJ is partly Cav2.1 channel-dependent, whereas evoked release relies entirely on Cav2.1 channels. Studies on the Cav2.1 mouse mutant Rolling Nagoya show that spontaneous and evoked neurotransmitter release are controlled independently. Studies on mouse mutants that lack auxiliary Cav2.1 channel subunits revealed that these subunits are redundant and/or absent at the mouse NMJ. The studies presented in this thesis provide novel insights into the synaptic dysfunction caused by Cav2.1 channel mutations. Synaptic effects on central synapses are likely to share many features with those observed at the mouse NMJ and thought to underlie (some of) the neurological symptoms of human and mouse disorders associated with Cav2.1 channel dysfunction