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

Publication Type	Academic Article
Authors	Carrillo-Reid L, Day M, Xie Z, Melendez A, Kondapalli J, Plotkin J, Wokosin D, Chen Y, Kress G, Kaplitt M, Ilijic E, Guzman J, Chan C, Surmeier D
Journal	Elife
Volume	8
Date Published	04/24/2019
ISSN	2050-084X
Keywords	Corpus Striatum, Huntingtin Protein, Huntington Disease, Mutant Proteins, Neurons, Shal Potassium Channels
Abstract	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.
DOI	10.7554/eLife.40818
PubMed ID	31017573
PubMed Central ID	PMC6481990