Melatonin Mitigates Sleep Restriction-Induced Cognitive and Glymphatic Dysfunction Via Aquaporin-4 Polarization

Apr 28, 2025Molecular neurobiology

Melatonin may reduce thinking problems and brain fluid flow issues caused by sleep loss through improving water channel function

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Abstract

Chronic sleep restriction (SR) leads to significant cognitive deficits and disrupts the localization of aquaporin-4 (AQP4) in the brain.

SR impairs glymphatic clearance of toxic metabolites, which may contribute to brain dysfunction.
Melatonin (Mel) treatment improves cognitive function and restores AQP4 polarity in mice subjected to SR.
Mel enhances glymphatic transport and reduces levels of amyloid-beta and phosphorylated tau in the hippocampus of SR mice.
Melatonin decreases glial cell activation, pro-inflammatory cytokine production, and synaptic protein loss associated with SR.
The protective effects of Mel against SR-induced brain alterations are diminished in mice lacking AQP4.
Mel activates the vitamin D receptor, leading to increased expression of DTNA, which helps restore AQP4 polarization during chronic SR.

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Chronic sleep restriction (SR) impairs the glymphatic clearance of macromolecular toxic metabolites, which is associated with the loss of perivascular polarization of aquaporin-4 (AQP4). Melatonin (Mel) has been shown to maintain the circadian rhythm of AQP4 polarization. However, the role of AQP4 polarization in Mel's protective effects against SR-induced brain dysfunction remains unclear. In the present study, using a modified rotating rod SR mouse model, we demonstrated the time-dependent effect of SR on short-term memory deficits and AQP4 mislocalization in the hippocampus. Subsequent experiments characterized the dose-dependent pattern of Mel ameliorating SR-induced impairments of cognitive function and AQP4 polarity. Mel's treatment enhanced glymphatic transport in SR mice, as revealed by cerebrospinal tracer experiments, and reduced hippocampal amyloid-beta and phosphorylated tau levels. Additionally, Mel significantly decreased glial cell activation, pro-inflammatory cytokine production, and synaptic protein loss in the hippocampus of SR mice. However, in AQP4 knockout mice, Mel's protective effects against SR-induced pathophysiological alterations described above were largely abolished. Mechanistically, Mel activated the vitamin D receptor and then upregulated expression of DTNA (Dystrobrevin Alpha), a key component of the dystrophin-associated complex, which in turn restored AQP4 polarization during chronic SR conditions. This finding indicates that AQP4-mediated lymphatic clearance is necessary for Mel to combat chronic SR-induced brain impairment.

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Melatonin Mitigates Sleep Restriction-Induced Cognitive and Glymphatic Dysfunction Via Aquaporin-4 Polarization

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