Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of huntington's disease

Yumei Cao, David Bartolomé-Martín, Naama Rotem, Carlos Rozas, Shlomo S. Dellal, Marcelo A. Chacon, Bashkim Kadriu, Maria E. Gulinello, Kamran Khodakhah, Donald S. Faber

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

We describe a fast activity-dependent homeostatic regulation of intrinsic excitability of identified neurons in mouse dorsal striatum, the striatal output neurons. It can be induced by brief bursts of activity, is expressed on a time scale of seconds, limits repetitive firing, and can convert regular firing patterns to irregular ones. We show it is due to progressive recruitment of the KCNQ2/3 channels that generate the M current. This homeostatic mechanism is significantly reduced in striatal output neurons of the R6/2 transgenic mouse model of Huntington's disease, at an age when the neurons are hyperactive in vivo and the mice begin to exhibit locomotor impairment. Furthermore, it can be rescued by bath perfusion with retigabine, a KCNQ channel activator, and chronic treatment improves locomotor performance. Thus, M-current dysfunction may contribute to the hyperactivity and network dysregulation characteristic of this neurodegenerative disease, and KCNQ2/3 channel regulation may be a target for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)2239-2244
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number7
DOIs
StatePublished - Feb 17 2015

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Corpus Striatum
Huntington Disease
Locomotion
Neurons
Baths
Neurodegenerative Diseases
Transgenic Mice
Perfusion
Therapeutics

Keywords

  • Homeostasis
  • Huntington&aposs disease
  • Intrinsic excitability
  • KCNQ channels
  • M current

ASJC Scopus subject areas

  • General

Cite this

Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of huntington's disease. / Cao, Yumei; Bartolomé-Martín, David; Rotem, Naama; Rozas, Carlos; Dellal, Shlomo S.; Chacon, Marcelo A.; Kadriu, Bashkim; Gulinello, Maria E.; Khodakhah, Kamran; Faber, Donald S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 7, 17.02.2015, p. 2239-2244.

Research output: Contribution to journalArticle

Cao, Yumei ; Bartolomé-Martín, David ; Rotem, Naama ; Rozas, Carlos ; Dellal, Shlomo S. ; Chacon, Marcelo A. ; Kadriu, Bashkim ; Gulinello, Maria E. ; Khodakhah, Kamran ; Faber, Donald S. / Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of huntington's disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 7. pp. 2239-2244.
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