TY - JOUR
T1 - Rescue of homeostatic regulation of striatal excitability and locomotor activity in a mouse model of huntington's disease
AU - Cao, Yumei
AU - Bartolomé-Martín, David
AU - Rotem, Naama
AU - Rozas, Carlos
AU - Dellal, Shlomo S.
AU - Chacon, Marcelo A.
AU - Kadriu, Bashkim
AU - Gulinello, Maria
AU - Khodakhah, Kamran
AU - Faber, Donald S.
PY - 2015/2/17
Y1 - 2015/2/17
N2 - 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.
AB - 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.
KW - Homeostasis
KW - Huntington&aposs disease
KW - Intrinsic excitability
KW - KCNQ channels
KW - M current
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UR - http://www.scopus.com/inward/citedby.url?scp=84923164525&partnerID=8YFLogxK
U2 - 10.1073/pnas.1405748112
DO - 10.1073/pnas.1405748112
M3 - Article
C2 - 25646456
AN - SCOPUS:84923164525
SN - 0027-8424
VL - 112
SP - 2239
EP - 2244
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -