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Related Concept Videos

Huntington Disease l: Introduction01:21

Huntington Disease l: Introduction

Huntington disease or HD is a progressive, fatal neurodegenerative disorder inherited in an autosomal dominant pattern.PathophysiologyIt is caused by expansion of the CAG trinucleotide repeat in the HTT gene on chromosome 4 (4p16.3), producing an abnormal huntingtin protein with an expanded polyglutamine tract. This misfolded protein disrupts cellular function, leading to neuronal death. Normal alleles have ≤26 repeats, 27–35 are intermediate (risk of expansion), 36–39 show reduced penetrance,...

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Restoring Compromised Cl- in D2 Neurons of a Huntington's Disease Mouse Model Rescues Motor Disability.

Melissa Serranilla1, Jessica C Pressey1, Melanie A Woodin2

  • 1Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|November 5, 2024
PubMed
Summary

In Huntington's disease (HD), chloride regulation is impaired in dopamine 2 receptor-expressing neurons, contributing to their early degeneration. Restoring chloride transport in these neurons delays motor symptoms in mice.

Keywords:
GABAHuntington’s diseaseMSNselectrophysiologysynaptic inhibition

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Huntington's disease (HD) is a progressive neurodegenerative disorder impacting striatal medium spiny neurons (MSNs).
  • Early HD stages involve degeneration of dopamine 2 receptor-expressing MSNs (D2 MSNs) before dopamine 1 receptor-expressing MSNs (D1 MSNs).
  • The role of potassium chloride cotransporter 2 (KCC2) in regulating chloride (Cl-) and GABAergic signaling in HD MSNs remains uncharacterized.

Purpose of the Study:

  • To investigate differential alterations in Cl- regulation in D1 and D2 MSNs during early symptomatic HD.
  • To determine if KCC2 dysfunction contributes to the selective vulnerability of D2 MSNs in HD.
  • To explore KCC2 as a potential therapeutic target for delaying HD progression.

Main Methods:

  • Electrophysiology was used to measure the reversal potential for GABA-A receptors (E GABA) in striatal D1 and D2 MSNs from R6/2 mice.
  • KCC2 was overexpressed in D2 MSNs using adeno-associated virus (AAV)-mediated delivery.
  • Motor function was assessed to evaluate the impact of KCC2 manipulation on HD phenotypes.

Main Results:

  • Early symptomatic HD (P55-P65) in R6/2 mice showed impaired Cl- regulation specifically in D2 MSNs, with no changes in D1 MSNs.
  • Dysfunctional Cl- regulation in the globus pallidus externa led to GABA-mediated excitation.
  • Overexpression of KCC2 in D2 MSNs delayed the onset of motor impairments in R6/2 mice.

Conclusions:

  • Cl- homeostasis is differentially disrupted in D1 and D2 MSNs during HD progression.
  • Impaired KCC2 function in D2 MSNs contributes to their enhanced susceptibility and degeneration in HD.
  • Targeting KCC2-mediated Cl- regulation offers a potential therapeutic strategy for mitigating early HD motor deficits.