Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment

Strong epidemiological and experimental evidence indicates that hypertension has detrimental effects on the cerebral microcirculation and thereby promotes accelerated brain aging. Hypertension is an independent risk factor for both vascular cognitive impairment (VCI) and Alzheimer's disease (AD). However, the pathophysiological link between hypertension-induced cerebromicrovascular injury (e.g., blood-brain barrier disruption, increased microvascular oxidative stress, and inflammation) and cognitive decline remains elusive. The present study was designed to characterize neuronal functional and morphological alterations induced by chronic hypertension and compare them to those induced by aging. To achieve that goal, we induced hypertension in young C57BL/6 mice by chronic (4 weeks) infusion of angiotensin II. We found that long-term potentiation (LTP) of performant path synapses following high-frequency stimulation of afferent fibers was decreased in hippocampal slices obtained from hypertensive mice, mimicking the aging phenotype. Hypertension and advanced age were associated with comparable decline in synaptic density in the stratum radiatum of the mouse hippocampus. Hypertension, similar to aging, was associated with changes in mRNA expression of several genes involved in regulation of neuronal function, including down-regulation of Bdnf, Homer1, and Dlg4, which may have a role in impaired synaptic plasticity. Collectively, hypertension impairs synaptic plasticity, reduces synaptic density, and promotes dysregulation of genes involved in synaptic function in the mouse hippocampus mimicking the aging phenotype. These hypertension-induced neuronal alterations may impair establishment of memories in the hippocampus and contribute to the pathogenesis and clinical manifestation of both vascular cognitive impairment (VCI) and Alzheimer's disease (AD).