Description:

Michelle Day, Ph.D.
Research Associate Professor
Department of Physiology
Feinberg School of Medicine

The early stages of Huntington’s disease (HD) are 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. In tissue from symptomatic mice, distal dendrites of iSPNs from HD mice were hypoexcitable. I will present new data showing that the hypoexcitability was attributable to increased opening of dendritic Kv4 K+ channels, stemming from a greater association with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor (TrkBR) signaling, which was previously shown to be impaired in HD models. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels and by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a virally-delivered zinc finger protein (ZFP). Thus, our studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the hyperkinetic motor symptoms of HD. Furthermore, the rescue of both dendritic excitability and synaptic plasticity by striatal suppression of mHtt transcription with ZFP points us to a promising potential treatment for people suffering from this devastating disorder.