Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension

Glutamatergic synaptic input in the hypothalamic paraventricular nucleus (PVN) plays a critical role in regulating sympathetic outflow in hypertension.GluR2-lackingAMPAreceptors(AMPARs)arepermeabletoCa ²⁺,andtheir currentsshowuniqueinwardrectification.However, little is known about changes in theAMPARcomposition and its functional significance in hypertension. In this study, we found that AMPARmediated EPSCs (AMPAR-EPSCs) of retrogradely labeled spinally projecting PVN neurons exhibited a linear current-voltage relationship in Wistar-Kyoto (WKY) rats. However, AMPAR-EPSCs of labeled PVN neurons in spontaneously hypertensive rats (SHR) displayed inward rectification at positive holding potentials, which were not altered by lowering blood pressure with celiac ganglionectomy. Blocking GluR2-lacking AMPARs with 1-naphthyl acetyl spermine (NAS) caused a greater reduction in the AMPAR-EPSC amplitude and firing activity of PVN neurons in SHR than inWKYrats. Furthermore, blockingNMDAreceptors and inhibition of calpain or calcineurin abolished inward rectification ofAMPAR-EPSCsofPVNneuronsinSHR.TheGluR2protein levelwassignificantly less in theplasmamembranebutgreater in the cytosolic vesicle fraction in SHR than in WKY rats. In addition, microinjection of NAS into the PVN decreased blood pressure and lumbar sympathetic nerve activity in SHR but not inWKYrats. Our study reveals that increased GluR2-lackingAMPARactivity of PVN neurons results from GluR2 internalization throughNMDAreceptor-calpain-calcineurin signaling in hypertension. This phenotype switch in synaptic AMPARs contributes to increased excitability of PVN presympathetic neurons and sympathetic vasomotor tone in hypertension.