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Single Synapse Indicators of Glutamate Release and Uptake in Acute Brain Slices from Normal and Huntington Mice
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Microarray profiling of hypothalamic gene expression changes in Huntington's disease mouse models.

Elna Dickson1, Amoolya Sai Dwijesha2, Natalie Andersson3

  • 1Biomarkers in Brain Disease, Department of Experimental Medical Science, Lund University, Lund, Sweden.

Frontiers in Neuroscience
|November 21, 2022
PubMed
Summary

Huntington's disease (HD) affects the hypothalamus, altering gene expression. Both wild-type and mutant huntingtin (HTT) impact hypothalamic pathways, with mutant HTT disrupting neuroendocrine networks crucial for feeding behavior.

Keywords:
HD mouse modelsHuntington’s diseasedifferential expressionhuntingtinhypothalamusmicroarrayneuroendocrine

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Huntington's disease (HD) is a neurodegenerative disorder linked to CAG repeat expansion in the huntingtin (HTT) gene.
  • Hypothalamic structural changes and neuropathology are implicated in HD's non-motor symptoms.

Purpose of the Study:

  • To investigate the transcriptional effects of hypothalamic HTT expression in HD mouse models.
  • To determine how wild-type HTT (wtHTT) and mutant HTT (mHTT) expression influence hypothalamic gene expression profiles.

Main Methods:

  • RNA sequencing of hypothalamic tissue from BACHD mice (ubiquitous mHTT) and mice with targeted hypothalamic wtHTT or mHTT overexpression.
  • Gene Set Enrichment Analysis (GSEA) and quantitative real-time PCR (qRT-PCR) for gene expression validation.

Main Results:

  • Hypothalamic wtHTT and mHTT overexpression led to significant transcriptional changes, including suppressed sterol and cholesterol metabolism.
  • mHTT overexpression distinctly suppressed neuroendocrine networks, downregulating neuropeptides (Hcrt, Tacr3, Cart) and catecholamine-related genes (Ddc, Hdc, Th, Vip).
  • BACHD mice showed moderate hypothalamic transcriptomic changes, with inflammatory and gonadotropin pathways enriched at 10 months.

Conclusions:

  • Both wtHTT and mHTT overexpression alter the hypothalamic transcriptome.
  • mHTT specifically disrupts neuroendocrine circuits involved in feeding behavior.
  • Ubiquitous full-length mHTT expression has a moderate impact on the BACHD hypothalamus transcriptome compared to targeted overexpression.