Cerebellar Ataxia by Enhanced Ca_v2.1 Currents Is Alleviated by Ca²-Dependent K-Channel Activators in Cacnala^S218L Mutant Mice.

Zhenyu Gao; Todorov, Boyan; Barrett, Curtis F.; van Dorp, Stijn; Ferrari, Michel D.; van den Maagdenberg, Arn M.J.M.; De Zeeuw, Chris I.; Hoebeek, Freek E.

Mutations in the CACNA1A gene are associated with neurological disorders, such as ataxia, hémiplégie migraine, and epilepsy. These mutations affect the pore-forming a1A-subunit of Cav2.1 channels and thereby either decrease or increase neuronal Ca2 influx. A decreased Cav2.1 -mediated Ca2 influx has been shown to reduce the regularity of cerebellar Purkinje cell activity and to induce episodic cerebellar ataxia. However, little is known about how ataxia can be caused by CACNA1A mutations that increase the Ca2 influx, such as the S218L missense mutation. Here, we demonstrate that the S218L mutation causes a negative shift of voltage dependence of Cav2.1 channels of mouse Purkinje cells and results in lowered thresholds for somatic action potentials and dendritic Ca2 spikes and in disrupted firing patterns. The hyperexcitability of CacnalaS2laL Purkinje cells was counteracted by application of the activators of Ca2 -dependent K channels, 1-EBIO and chlorzoxazone (CHZ). Moreover, 1-EBIO also alleviated the irregularity of Purkinje cell firing both in vitro and in vivo, while CHZ improved the irregularity of Purkinje cell firing in vitro as well as the motor performance of Cacnalas2I8L mutant mice. The current data suggest that abnormalities in Purkinje cell firing contributes to cerebellar ataxia induced by the S218L mutation and they advocate a general therapeutic approach in that targeting Ca2 -dependent K channels may be beneficial for treating ataxia not only in patients suffering from a decreased Ca2 influx, but also in those suffering from an increased Ca2 influx in their Purkinje cells.

NEUROLOGICAL research; GENETIC mutation; NEUROLOGICAL emergencies; MIGRAINE; EPILEPSY; CEREBELLAR ataxia; CHLORZOXAZONE; LABORATORY mice

Journal of Neuroscience, 2012, Vol 32, Issue 44, p15533

0270-6474

Academic Journal

10.1523/JNEUROSCI.2454-12.2012