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

Luis Carrillo-Reid, Michelle Day, Zhong Xie, Alexandria E. Melendez, Jyothisri Kondapalli, Joshua L. Plotkin, David L. Wokosin, Yu Chen, Geraldine J. Kress, Michael Kaplitt, Ema Ilijic, Jaime N. Guzman, C. Savio Chan, D. James Surmeier*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Article numbere40818
JournaleLife
Volume8
DOIs
StatePublished - Apr 2019

Funding

We thank Dr. Vivian Hernandez for initial characterization of the Kv4.2 shRNA. Sasha Ulrich for technical assistance. This work was supported by CHDI (DJS), JPB (DJS and MK), and NIH (NS 069777 to CSC and NS 34696 to DJS).

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

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