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Pathophysiology in the suprachiasmatic nucleus in mouse models of Huntington's disease
Dika Kuljis1,2, Takashi Kudo3,4, Yu Tahara3
1Department of Neurobiology, University of California Los Angeles, Los Angeles, California.
Insights
Huntington's disease (HD) disrupts circadian rhythms by impairing suprachiasmatic nucleus (SCN) neurons. Enhanced large-conductance calcium-activated potassium (BK) currents contribute to this early pathophysiology in HD mouse models.
Area of Science:
- Neuroscience
- Chronobiology
- Genetics
Background:
- Sleep-wake cycle disturbances are common in Huntington's disease (HD).
- The mechanisms underlying these disruptions, particularly the role of the central circadian clock (suprachiasmatic nucleus, SCN), are not fully understood.
- HD mouse models display disrupted rhythms and reduced SCN neural activity.
Purpose of the Study:
- To investigate the ionic mechanisms responsible for reduced SCN neural activity in HD.
- To determine if SCN pathophysiology occurs early in HD progression.
- To identify specific ion channels involved in SCN dysfunction in HD.
Main Methods:
- Electrophysiological techniques were used to record neural activity in SCN neurons from BACHD and Q175 HD mouse models.
- Resting membrane potential and potassium currents were analyzed.
- Expression of the BK channel subunit (Kcnma1) was examined.
- Direct current injection and N-methyl-d-aspartate (NMDA) application were used to test neuronal excitability.
Main Results:
- SCN neural activity rhythms and daily variations in resting membrane potential were lost early in HD progression in BACHD mice.
- Reduced SCN neural activity in mutants could be transiently restored.
- Mutant SCN neurons exhibited enhanced large-conductance calcium-activated potassium (BK) currents.
- Increased expression of the Kcnma1 subunit of the BK channel was observed in mutant SCN.
- Similar findings of decreased activity and enhanced BK currents were observed in the Q175 HD mouse model.
Conclusions:
- SCN neurons show early signs of pathophysiology in both BACHD and Q175 HD mouse models.
- Dysregulation of BK currents, specifically enhancement, is implicated in the reduced SCN neural activity observed in HD.
- These findings highlight a potential target for therapeutic interventions aimed at correcting circadian rhythm disturbances in HD.
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.