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Elife. 2019 Apr 24;8. pii: e40818. doi: 10.7554/eLife.40818.

Mutant huntingtin enhances activation of dendritic Kv4 K+ channels in striatal spiny projection neurons.

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Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
Department of Developmental Neurobiology and Neurophysiology, Neurobiology Institute, National Autonomous University of Mexico, Queretaro, Mexico.
Department of Neurobiology & Behavior, Stony Brook University School of Medicine, Stony Brook, United States.
Department of Neurology, Washington University School of Medicine, St. Louis, United States.
Department of Neurological Surgery, Weill Cornell Medical College, New York, United States.


Huntington's disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD.


Huntington's disease; KChIP; Kv4; calcium imaging; dendrite; mouse; neuroscience; zinc finger protein

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