Pathophysiology in the suprachiasmatic nucleus in mouse models of Huntington’s disease

Dika Kuljis, Takashi Kudo, Yu Tahara, Cristina A. Ghiani, Christopher S. Colwell

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, are not well established. The BACHD mouse model of HD exhibits disrupted behavioral and physiological rhythms, including decreased electrical activity in the central circadian clock (suprachiasmatic nucleus, SCN). In this study, electrophysiological techniques were used to explore the ionic underpinning of the reduced spontaneous neural activity in male mice. We found that SCN neural activity rhythms were lost early in the disease progression and was accompanied by loss of the normal daily variation in resting membrane potential in the mutant SCN neurons. The low neural activity could be transiently reversed by direct current injection or application of exogenous N-methyl-d-aspartate (NMDA) thus demonstrating that the neurons have the capacity to discharge at WT levels. Exploring the potassium currents known to regulate the electrical activity of SCN neurons, our most striking finding was that these cells in the mutants exhibited an enhancement in the large-conductance calcium activated K+ (BK) currents. The expression of the pore forming subunit (Kcnma1) of the BK channel was higher in the mutant SCN. We found a similar decrease in daytime electrical activity and enhancement in the magnitude of the BK currents early in disease in another HD mouse model (Q175). These findings suggest that SCN neurons of both HD models exhibit early pathophysiology and that dysregulation of BK current may be responsible.

Original languageEnglish
Pages (from-to)1862-1875
Number of pages14
JournalJournal of Neuroscience Research
Volume96
Issue number12
DOIs
Publication statusPublished - 2018 Dec 1
Externally publishedYes

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Keywords

  • BACHD
  • BK current
  • circadian rhythms
  • Huntington’s disease
  • Q175
  • suprachiasmatic nucleus

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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