α2δ-1–Dependent NMDA Receptor Activity in the Hypothalamus Is an Effector of Genetic-Environment Interactions That Drive Persistent Hypertension

Abstract

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.

Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow

“…Another important finding of our study is that calcineurin inhibition augments NMDAR activity at both presynaptic and postsynaptic sites in the PVN to cause hyperactivity of PVN presympathetic neurons. This is supported by our findings that the NMDAR-mediated 25,27,29 The increased presynaptic glutamate release subsequently acts on postsynaptic NMDARs and AMPARs to increase the excitability of PVN presympathetic neurons in CIH. Thus, NMDARs and AMPARs have overlapping roles in augmenting glutamatergic input in the PVN in CIH.…”

“…Presynaptic NMDARs in the PVN are latent and not functionally active under normotensive conditions, but they become tonically activated to potentiate synaptic glutamate release in hypertensive conditions. 25,27,29 The increased presynaptic glutamate release subsequently acts on postsynaptic NMDARs and AMPARs to increase the excitability of PVN presympathetic neurons in CIH. Thus, NMDARs and AMPARs have overlapping roles in augmenting glutamatergic input in the PVN in CIH.…”

α2δ‐1 protein promotes synaptic expression of Ca2+ permeable–AMPA receptors by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension

“…In the present study, we found that GluA1/GluA2, but not GluA2/GluA3, heteromers were reduced in hypothalamic synaptosomes in SHR, which likely accounts for increased CP-AMPARs in hypertension. We have shown previously that α2δ-1 is upregulated and mediates potentiated synaptic NMDAR activity of PVN presympathetic neurons in hypertension Zhou, Shao, et al, 2021).…”

“…In contrast, α2δ-1 seems to favor the assembly of GluA1 homotetramers by preferentially inhibiting GluA1/GluA2 heteromeric assembly in the ER, thereby facilitating synaptic incorporation of CP-AMPARs (Li et al, 2021). Accordingly, α2δ-1 has a remarkable ability to synergistically augment Ca (Zhou, Shao, et al, 2021). α2δ-1CT peptide likely attenuates synaptic activity of both NMDARs and CP-AMPARs in SHR, because the C terminus of α2δ-1 is essential for α2δ-1 interaction with AMPARs and NMDARs (Li et al, 2021;Chen et al, 2018).…”

“…α2δ-1 is also upregulated in the hypothalamus and potentiates sympathetic outflow in hypertension Zhou, Zhou, Shao, et al, 2021). Thus, we determined whether α2δ-1 plays a role in diminished GluA1/GluA2 heteromers in the hypothalamus in SHR.…”