a2d-1–dependent NMDA receptor activity in the hypothalamus is an effector of genetic-environment interactions that drive persistent hypertension

Jing Jing Zhou, Jian Ying Shao, Shao Rui Chen, De Pei Li, Hui Lin Pan

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)6551-6563
Number of pages13
JournalJournal of Neuroscience
Issue number30
StatePublished - Jul 28 2021


  • Autonomic nervous system
  • Depression
  • Gabapentinoids
  • Neurogenic hypertension
  • Stress
  • Sympathetic nervous system

ASJC Scopus subject areas

  • Neuroscience(all)


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