Abstract
Hereditary ataxic mice, tottering (tg) and rolling Nagoya (tg(rol)), carry mutations in the P/Q-type Ca(2+) channel alpha(1A) subunit gene. The positions of the mutations and the neurological phenotypes are known, but the mechanisms of how the mutations cause the symptoms and how the different mutations lead to various onset and severity have remained unsolved. Here we compared fundamental properties of excitatory synaptic transmission in the cerebellum and roles of Ca(2+) channel subtypes therein among wild-type control, tg, and tg(rol) mice. The amplitude of EPSC of the parallel fiber-Purkinje cell (PF-PC) synapses was considerably reduced in ataxic tg(rol). Although the amplitude of the parallel fiber-mediated EPSC was only mildly decreased in young non-ataxic tg mice, it was drastically diminished in adult ataxic tg mice of postnatal day 28-35, showing a good correlation between the impairment of the PF-PC synaptic transmission and manifestation of ataxia. In contrast, the EPSC amplitude of the climbing fiber-Purkinje cell (CF-PC) synapses was preserved in tg, and it was even increased in tg(rol), which was associated with altered properties of the postsynaptic glutamate receptors. The climbing fiber-mediated EPSC was more dependent on other Ca(2+) channel subtypes in mutant mice, suggesting that such compensatory mechanisms contribute to maintaining the CF-PC synaptic transmission virtually intact. The results indicate that different mutations of the P/Q-type Ca(2+) channel not only cause the primary effect of different severity but also lead to diverse additional secondary effects, resulting in disruption of well balanced neural networks.