Into the depths of ataxia

Abstract

Ataxia is a lethal neurological disease characterized by incoordination, postural abnormalities, difficulties with gait, and problems with clarity of speech. The etiology of ataxia is divided equally between hereditary and sporadic forms. Regardless of cause, the cerebellar cortex is often a target in ataxia. Thus, how a disruption in cerebellar cortex might lead to ataxia is of considerable interest. A report in this issue of the JCI links ataxia to enhanced hyperexcitability of neurons in the deep cerebellar nuclei.

Figure 1

SK3-B1 mice demonstrate a direct relationship between DCN firing rate and proper movement control. In the normal state (a), Purkinje cells in the cerebellar cortex provide an inhibitory signal to DCN neurons, which, in conjunction with other pathways into the DCN, results in a normal DCN firing rate and proper motor control. In cerebellar ataxia (b), the inhibitory signal to the DCN neurons from Purkinje cells is compromised. This lack of a proper inhibition was suggested to result in an increased firing rate of DCN neurons, leading to ataxia. (c) The direct relationship between increased DCN firing rate and ataxia was demonstrated by Shakkottai et al. (4). When the SK inhibitor SK3-B1 was expressed in DCN neurons, those neurons had an increased firing rate and the transgenic mice were ataxic. Importantly, the Purkinje cell input into the DCN remained intact in the SK3-B1 mice.