Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of Huntington’s disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-02, Vol.112 (7), p.2239-2244
• Main Authors: Cao, Yumei, Bartolomé-Martín, David, Rotem, Naama, Rozas, Carlos, Dellal, Shlomo S., Chacon, Marcelo A., Kadriu, Bashkim, Gulinello, Maria, Khodakhah, Kamran, Faber, Donald S.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Corpus Striatum - physiopathology; Disease Models, Animal; Homeostasis; Homesteading; Huntington Disease - physiopathology; Huntingtons disease; Locomotion; Mice; Neurons; Rodents
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1405748112

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. Significance Neurons typically regulate their intrinsic excitability to prevent excessive excitation and to gate information transfer. This paper describes an activity-dependent decrease in intrinsic excitability following brief bursts of nerve impulses. This homeostatic mechanism, due to the recruitment, or sensitization, of voltage-gated potassium channels, the KCNQ2/3 channels, is reduced in striatal neurons of two transgenic mouse models of Huntington’s disease at an age when these neurons are hyperactive and motor symptoms begin to appear. Pharmacological activation of these channels restores homeostasis in transgenic neurons, in vitro, and reduces motor impairment in behaving mice, consistent with the hypothesis that hyperactivity enables establishment of dysfunctional neural circuits and that KCNQ channels could serve as therapeutic targets for the treatment of HD.