Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function

Prolonged intake of excessive amounts of ethanol is known to have adverse effects on the central nervous system (CNS). Here we investigated the effects of acute and chronic ethanol exposure and withdrawal from chronic ethanol exposure on glymphatic function, which is a brain-wide metabolite clearance system connected to the peripheral lymphatic system. Acute and chronic exposure to 1.5 g/kg (binge level) ethanol dramatically suppressed glymphatic function in awake mice. Chronic exposure to 1.5 g/kg ethanol increased GFAP expression and induced mislocation of the astrocyte-specific water channel aquaporin 4 (AQP4), but decreased the levels of several cytokines. Surprisingly, glymphatic function increased in mice treated with 0.5 g/kg (low dose) ethanol following acute exposure, as well as after one month of chronic exposure. Low doses of chronic ethanol intake were associated with a significant decrease in GFAP expression, with little change in the cytokine profile compared with the saline group. These observations suggest that ethanol has a J-shaped effect on the glymphatic system whereby low doses of ethanol increase glymphatic function. Conversely, chronic 1.5 g/kg ethanol intake induced reactive gliosis and perturbed glymphatic function, which possibly may contribute to the higher risk of dementia observed in heavy drinkers.