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Striatal Direct and Indirect Pathway Output Structures Are Differentially Altered in Mouse Models of Huntington's
Joshua Barry1, Garnik Akopian1, Carlos Cepeda1
1Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, Brain Research Institute, University of California-Los Angeles, Los Angeles, California 90095.
Summary
Huntington's disease (HD) disrupts communication in the brain's output pathways. This study reveals imbalances in synaptic activity affecting motor function in HD mouse models.
Area of Science:
- Neuroscience
- Synaptic Plasticity
- Neurodegenerative Diseases
Background:
- Huntington's disease (HD) primarily affects striatal medium-sized spiny neurons (MSNs).
- The impact of striatal changes on downstream output structures like the substantia nigra pars reticulata (SNr) and external globus pallidus (GPe) is less understood.
- Understanding these downstream effects is crucial for explaining HD-related motor dysfunction.
Purpose of the Study:
- To investigate synaptic communication alterations in the direct and indirect output pathways of the striatum in mouse models of HD.
- To examine the functional consequences of these alterations on the SNr and GPe.
- To identify potential mechanisms contributing to motor deficits in Huntington's disease.
Main Methods:
- Utilized two mouse models of Huntington's disease (R6/2 and YAC128).
- Employed Cre recombination, optogenetics, and whole-cell patch-clamp recordings.
- Assessed intrinsic and synaptic properties of SNr and GPe neurons in symptomatic and presymptomatic HD mice.
Main Results:
- Reduced amplitude of GABAergic responses in SNr neurons due to direct pathway MSN terminal stimulation in symptomatic HD mice.
- Decreased spontaneous GABA synaptic activity observed in SNr neurons.
- Differential effects noted: GPe neurons showed altered GABA response decay times, while SNr neurons exhibited changes in membrane properties and synaptic responses.
- Indirect pathway MSN activation evoked larger responses in direct pathway MSNs.
Conclusions:
- Demonstrated differential disruption of synaptic communication in the direct and indirect striatal output pathways targeting SNr and GPe.
- These disruptions lead to an imbalance in striatal output.
- The findings highlight a critical mechanism contributing to motor dysfunction in Huntington's disease.
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01:11Direct Motor Pathways
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01:22Indirect Motor Pathways
The indirect motor or extrapyramidal pathways originate in the brainstem, the lower portion of the brain that connects it to the spinal cord. They consist of several distinct tracts, each with specialized functions. The four main tracts of the indirect motor pathways are the vestibulospinal tract, the reticulospinal tract, the tectospinal tract, and the rubrospinal tract.
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01:21Huntington 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,...