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Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington's disease transgenic mice
G J Klapstein1, R S Fisher, H Zanjani
1Mental Retardation Research Center, University of California, Los Angeles, California 90095, USA.
Journal of Neurophysiology
|December 4, 2001
Summary
Huntington's disease (HD) mouse models show few early changes in medium spiny neurons but significant electrophysiological and morphological alterations in symptomatic stages, impacting basal ganglia function and suggesting therapeutic targets.
Area of Science:
- Neuroscience
- Cellular Electrophysiology
- Neurodegenerative Diseases
Background:
- Huntington's disease (HD) is a progressive neurodegenerative disorder.
- Medium-sized spiny neurons are critical components of the basal ganglia circuitry.
- The R6/2 transgenic mouse model recapitulates key features of HD.
Purpose of the Study:
- To investigate electrophysiological and morphological changes in medium-sized spiny neurons in R6/2 mice at pre-symptomatic and symptomatic stages.
- To compare these changes with age-matched wild-type (WT) controls.
- To identify potential therapeutic targets for HD.
Main Methods:
- Intracellular recordings from medium-sized spiny neurons in brain slices.
- Electrophysiological analysis of passive and active membrane properties.
- Synaptic response characterization, including excitatory postsynaptic potentials (EPSPs).
- Morphological analysis using biocytin filling or Golgi staining.
Main Results:
- Presymptomatic R6/2 mice showed minor changes: increased input resistance and lower rheobase.
- Symptomatic R6/2 mice exhibited depolarized resting potentials, increased input resistance, decreased membrane time constants, and altered action potentials.
- EPSPs in symptomatic R6/2 mice required higher stimulus intensity, had slower rise times, and prolonged decay, suggesting N-methyl-D-aspartate receptor involvement.
- Reduced paired-pulse facilitation was observed in both pre- and symptomatic R6/2 mice.
- Morphological analysis revealed decreased dendritic spine density, smaller dendritic shaft diameters, and reduced dendritic fields in symptomatic R6/2 mice.
Conclusions:
- Significant alterations in passive and active membrane properties and synaptic function of medium-sized spiny neurons occur during HD progression in R6/2 mice.
- These physiological and morphological changes disrupt basal ganglia circuitry communication.
- The identified alterations provide potential targets for pharmacotherapies aimed at alleviating HD symptoms.
