Hypertension‐induced impairment in synaptic plasticity and dysregulation of genes involved in synaptic function in the mouse hippocampus: implications for the pathogenesis of vascular cognitive impairment in aging

Abstract

Strong epidemiological and experimental evidence indicate that hypertension predisposes to cognitive decline in the elderly, but the underlying mechanisms remain elusive. Long‐term potentiation (LTP), defined as a long‐lasting increase in synaptic efficacy following high‐frequency stimulation of afferent fibers, is presumed to play an important role in the establishment and storage of memories in the hippocampus. The present study was designed to characterize the effects of hypertension on synaptic plasticity and the expression of genes involved in regulation of synaptic function in the hippocampus. Hypertension was induced in 3 and 24 month old C57BL/6 mice by chronic (4 weeks) infusion of angiotensin II. To determine whether hypertension compromises neuronal mechanisms of learning and memory, extracellular recordings were performed from acute hippocampal slices using multi‐electrode arrays. Field excitatory post‐synaptic potentials (fEPSPs) were invoked through stimulation of the performant path collaterals and obtained from the dentate gyrus area. We found that hypertension was associated with significant decreases in LTP, mimicking the aging phenotype. Synaptic density was decreased by hypertension, an effect that was exacerbated by aging. In aged mice hypertension decreased protein expression of NMDAR1 and NMDAR2A, whereas expression of GLUR1 and GLUR2 were unaffected. Hippocampal mRNA expression of genes involved in synaptic function was assessed using a targeted qPCR array. The hippocampal gene expression signature observed in hypertensive mice (including altered expression of Nptx2, Bdnf, Homer1, Stxbp1 (Munc‐18), Dlg4) provides important clues for subsequent studies to elucidate the mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of both vascular cognitive impairment (VCI) and Alzheimer's disease.Support or Funding InformationThis work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on Aging