Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia

Vikram G. Shakkottai, Chin Hua Chou, Salvatore Oddo, Claudia A. Sailer, Hans Günther Knaus, George A. Gutman, Michael E. Barish, Frank M. LaFerla, K. George Chandy

Research output: Contribution to journalArticle

78 Citations (Scopus)

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 calcium-activated 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 (IAHP) 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.

Original languageEnglish (US)
Pages (from-to)582-590
Number of pages9
JournalJournal of Clinical Investigation
Volume113
Issue number4
DOIs
StatePublished - Feb 2004
Externally publishedYes

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Cerebellar Nuclei
Cerebellar Ataxia
Small-Conductance Calcium-Activated Potassium Channels
Riluzole
Apamin
Purkinje Cells
Neuroprotective Agents
Ataxia
Transgenes
Cerebellum
Transgenic Mice
Neurons

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shakkottai, V. G., Chou, C. H., Oddo, S., Sailer, C. A., Knaus, H. G., Gutman, G. A., ... Chandy, K. G. (2004). Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. Journal of Clinical Investigation, 113(4), 582-590. https://doi.org/10.1172/JCI200420216

Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. / Shakkottai, Vikram G.; Chou, Chin Hua; Oddo, Salvatore; Sailer, Claudia A.; Knaus, Hans Günther; Gutman, George A.; Barish, Michael E.; LaFerla, Frank M.; Chandy, K. George.

In: Journal of Clinical Investigation, Vol. 113, No. 4, 02.2004, p. 582-590.

Research output: Contribution to journalArticle

Shakkottai, VG, Chou, CH, Oddo, S, Sailer, CA, Knaus, HG, Gutman, GA, Barish, ME, LaFerla, FM & Chandy, KG 2004, 'Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia', Journal of Clinical Investigation, vol. 113, no. 4, pp. 582-590. https://doi.org/10.1172/JCI200420216
Shakkottai, Vikram G. ; Chou, Chin Hua ; Oddo, Salvatore ; Sailer, Claudia A. ; Knaus, Hans Günther ; Gutman, George A. ; Barish, Michael E. ; LaFerla, Frank M. ; Chandy, K. George. / Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. In: Journal of Clinical Investigation. 2004 ; Vol. 113, No. 4. pp. 582-590.
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