Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia

Abstract

Cerebellar ataxia, a devastating neurological disease, may be initiated by hyperexcitability of deep cerebellar nuclei (DCN) secondary to loss of inhibitory input from Purkinje neurons that frequently degenerate in this disease. This mechanism predicts that intrinsic DCN hyperexcitability would cause ataxia in the absence of upstream Purkinje degeneration. We report the generation of a transgenic (Tg) model that supports this mechanism of disease initiation. Small-conductance calciumactivated potassium (SK) channels, regulators of firing frequency, were silenced in the CNS of Tg mice with the dominant-inhibitory construct SK3-1B-GFP. Transgene expression was restricted to the DCN within the cerebellum and was detectable beginning on postnatal day 10, concomitant with the onset of cerebellar ataxia. Neurodegeneration was not evident up to the sixth month of age. Recordings from Tg DCN neurons revealed loss of the apamin-sensitive after-hyperpolarization current (I AHP ) and increased spontaneous firing through SK channel suppression, indicative of DCN hyperexcitability. Spike duration and other electrogenic conductance were unaffected. Thus, a purely electrical alteration is sufficient to cause cerebellar ataxia, and SK openers such as the neuroprotective agent riluzole may reduce neuronal hyperexcitability and have therapeutic value. This dominant-inhibitory strategy may help define the in vivo role of SK channels in other neuronal pathways.

Into the depths of ataxia

“…Overall, the results reported by Shakkottai et al (4) provide genetic evidence that firmly supports the idea that, in vivo, the firing rate of DCN neurons is indeed regulated by SK channels. These data go a long way toward removing any doubt that may have existed as to the role of SK channels as regulators of DCN firing (10).…”

“…Even though the authors provided an excellent illustration of the immunohistochemical scale used to assess expression levels (ref. 4, Figure 5b), some caution is warranted when the level of transgene expression is assessed solely by immunohistochemistry, which is relatively nonquantitative. Regardless, Shakkottai et al very nicely demonstrated that SK3-1B expression in DCN neurons correlates with an increase in their firing rate consistent with an increase in firing rate seen when SK channels were exposed to a pharmacological inhibitor.…”

“…Importantly, in this normal physiological process, changes in Purkinje cell and DCN firing rates are transient. In this issue of the JCI, Shakkottai et al explain that they hypothesized that perhaps a consistent increase in DCN excitability underlies the pathological state of cerebellar ataxia (4). In the case of a cerebellar ataxia, by whatever the cause, Purkinje cell function would be compromised and its inhibitory signal to neurons in the DCN would decrease, which in turn would increase DCN excitability.…”

“…To test this hypothesis directly, Shakkottai et al (4) increased the firing rate of DCN neurons in mice using a transgenic strategy. DCN cells, like many other neurons, express smallconductance calcium-activated potassium (SK) channels.…”

“…Shakkottai et al (4) had the foresight to tag the SK3-1B protein with GFP. This enabled them to use immunohistochemistry with antibodies to GFP to examine the cellular pattern of SK3-1B expression in the ataxic mice generated.…”