Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival

Cell Rep. 2020 Jan 21;30(3):642-657.e6. doi: 10.1016/j.celrep.2019.12.069.

Abstract

Huntington's disease (HD) is caused by an autosomal dominant polyglutamine expansion mutation of Huntingtin (HTT). HD patients suffer from progressive motor, cognitive, and psychiatric impairments, along with significant degeneration of the striatal projection neurons (SPNs) of the striatum. HD is widely accepted to be caused by a toxic gain-of-function of mutant HTT. However, whether loss of HTT function, because of dominant-negative effects of the mutant protein, plays a role in HD and whether HTT is required for SPN health and function are not known. Here, we delete Htt from specific subpopulations of SPNs using the Cre-Lox system and find that SPNs require HTT for motor regulation, synaptic development, cell health, and survival during aging. Our results suggest that loss of HTT function in SPNs could play a critical role in HD pathogenesis.

Keywords: Huntington's Disease; basal ganglia; neuronal survival; striatum; synaptic connectivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Animals
  • Behavior, Animal / physiology
  • Cell Survival
  • Corpus Striatum / physiology*
  • Gene Deletion
  • Globus Pallidus / physiology
  • Huntingtin Protein / metabolism*
  • Mice, Knockout
  • Motor Activity / physiology
  • Nerve Net / physiology*
  • Neurons / cytology*
  • Neurons / physiology*
  • Signal-To-Noise Ratio
  • Synapses / physiology*

Substances

  • Htt protein, mouse
  • Huntingtin Protein