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

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

doi:10.7554/elife.40818

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.

Highlights

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene (Zuccato et al, 2010)
Two genetic models of HD were used in these experiments: hemizygous BACHD mice (Andreet al., 2011; Gray et al, 2008) and heterozygous Q175 knock-in mice (Q175+/-) (Heikkinen et al, 2012; Menalled et al, 2012)
In two mouse models of HD (BACHD and Q175), the excitability of indirect pathway spiny projection neurons (iSPNs) distal dendrites fell in parallel with the emergence of motor deficits (~6 months old)

Summary

Introduction

HD is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin gene (Zuccato et al, 2010). At the outset of motor symptoms, HD patients have uncontrolled, choreic ‘dance-like’ movements. These symptoms are accompanied by down-regulation of phenotypic markers in striatal indirect pathway spiny projection neurons (iSPNs), which has led to the hypothesis that the hyperkinetic symptoms are due to a loss in indirect pathway function (Albin et al, 1992). Study of genetic HD models has implicated a large cast of potential factors that could be responsible. One of these factors is the loss of neurotrophic support (Gil and Rego, 2008). Mutant Htt (mHtt) induces deficits in the synthesis, transport and release of brain derived neurotrophic factor (BDNF) (Zuccato et al, 2010), as well as deficits in postsynaptic BDNF signaling through TrkB receptors (TrkBRs) (Gines et al, 2010; Plotkin et al, 2014)

Methods

Results

Conclusion