Volume-regulated anion channels (VRACs) are critically involved in regulating cell volume, and leucine-rich repeat-containing protein 8A (LRRC8A, SWELL1) is an obligatory subunit of VRACs. Cell swelling occurs early after brain ischemia, but it is unclear whether neuronal LRRC8a contributes to ischemia-induced glutamate release and brain injury. We found that Lrrc8a conditional knockout (Lrrc8a-cKO) mice produced by crossing Nestin Cre+/− with Lrrc8a flox+/+ mice died 7-8 weeks of age, indicating an essential role of brain LRRC8A for survival. Middle cerebral artery occlusion (MCAO) caused an early increase in LRRC8A protein levels in the hippocampus in wild-type (WT) mice. Whole-cell patch-clamp recording in brain slices revealed that oxygen-glucose deprivation significantly increased the amplitude of VRAC currents in hippocampal CA1 neurons in WT but not in Lrrc8a-cKO mice. Hypotonicity increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in hippocampal CA1 neurons in WT mice, and this was abolished by DCPIB, a VRAC blocker. But in Lrrc8a-cKO mice, hypotonic solution had no effect on the frequency of sEPSCs in these neurons. Furthermore, the brain infarct volume and neurological severity score induced by MCAO were significantly lower in Lrrc8a-cKO mice than in WT mice. In addition, MCAO-induced increases in cleaved caspase-3 and calpain activity, two biochemical markers of neuronal apoptosis and death, in brain tissues
The hypothalamic paraventricular nucleus (PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN presympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension. This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.
The interplay between genetic and environmental factors is critically involved in hypertension development. The paraventricular nucleus (PVN) of the hypothalamus regulates sympathetic output during stress responses and chronic hypertension. In this study, we determined mechanisms of synaptic plasticity in the PVN in chronic stress-induced persistent hypertension in male borderline hypertensive rats (BHR), the first offspring of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. In Wistar-Kyoto rats, chronic unpredictable mild stress (CUMS) increased arterial blood pressure (ABP) and heart rate, which quickly returned to baseline after CUMS ended. In contrast, in BHR, CUMS caused persistent elevation in ABP, which lasted at least 2 weeks after CUMS ended. CUMS also increased the mRNA level of a2d-1 and synaptic protein levels of GluN1, a2d-1, and a2d-1-GluN1 complexes in the PVN in BHR. Furthermore, CUMS significantly increased the frequency of miniature EPSCs and the amplitude of NMDAR currents in spinally projecting PVN neurons in BHR; these increases were normalized by blocking NMDARs with AP5, inhibiting a2d-1 with gabapentin, or disrupting the a2d-1-NMDAR interaction with a2d-1Tat peptide. Microinjection of AP5 or a2d-1Tat peptide into the PVN normalized elevated ABP and renal sympathetic nerve activity in stressed BHR. In addition, systemically administered gabapentin or memantine attenuated higher ABP induced by CUMS in BHR. Our findings indicate that chronic stress-induced persistent hypertension is mediated by augmented sympathetic outflow via a2d-1-bound NMDARs in the PVN. This new information provides a cellular and molecular basis for how the genetic-environment interactions cause persistent hypertension.
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