Hypertensive mice with over-expression of endothelin-1 show hyperactivity, impaired sensorimotor gating, mild cognitive deficit and cerebral vascular oxidative stress

Abstract

Previous studies showed that endothelin-1 (ET-1), a potent vasoconstrictor, is increased in the cerebrospinal fluid of dementia patients, suggesting that ET-1 might contribute to the impairment of cognitive function. This is supported by the observation that injection of ET-1 into the hippocampus of aged animals caused neuronal death, accompanied by learning and memory deficit. Since short-term effects of exogenously administered ET-1 may not stimulate the pathophysiological increase of ET-1, we examined the behavior of transgenic (TET-1) mice that overexpress ET-1 specifically in the endothelial cells. The behavioral changes and cognitive function were investigated in young (5-6 months) and aged (21-23 months) TET-1 mice under normal rearing conditions. Compared to the age-matched non-transgenic mice, the aged TET-1 mice displayed significantly higher locomotor activity in open field test, impairment in sensorimotor gating in pre-pulse inhibition of the acoustic startle response test, and a trend of spatial learning and memory deficit in Morris water maze test. The aged TET-1 mice also showed increased expression of heat-shock protein 70 (Hsp-70), hypoxia induced factor-1 alpha (HIF-1 alpha) and gp91phox, a subunit of NADPH oxidase, in the endothelial cells of cerebral vessels of the prefrontal cortex, suggesting that over-expression of endothelial ET-1 induces oxidative stress. In addition, glutamate expression was also increased in the prefrontal cortex of the aged TET-1 mice, suggesting that glutamate neurotransmission was also affected. These changes might account for the hyperactivity, impaired sensorimotor gating and mild cognitive deficit due to over-expression of ET-1 in the cerebrovascular endothelial cells.