mGluR5 Upregulation Increases Excitability of Hypothalamic Presympathetic Neurons through NMDA Receptor Trafficking in Spontaneously Hypertensive Rats

Abstract

The hypothalamic paraventricular nucleus (PVN) is critically involved in elevated sympathetic output and the development of hypertension. However, changes in group I metabotropic glutamate receptors (mGluR1 and mGluR5) and their relevance to the hyperactivity of PVN presympathetic neurons in hypertension remain unclear. Here, we found that selectively blocking mGluR5 significantly reduced the basal firing activity of spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs), but not in normotensive WistarKyoto (WKY) rats. However, blocking mGluR1 had no effect on the firing activity of PVN neurons in either group. The mRNA and protein levels of mGluR5 in the PVN and rostral ventrolateral medulla were significantly higher in SHRs than in WKY rats. The group I mGluR selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) similarly increased the firing activity of PVN neurons in WKY rats and SHRs. In addition, blocking NMDA receptors (NMDARs) through bath application or intracellular dialysis not only decreased the basal firing in SHRs, but also eliminated DHPG-induced excitation of spinally projecting PVN neurons. DHPG significantly increased the amplitude of NMDAR currents without changing their decay kinetics. Interestingly, DHPG still increased the amplitude of NMDAR currents and caused reappearance of functional NMDAR channels after initially blocking NMDARs. In addition, protein kinase C (PKC) inhibition or intracellular dialysis with synaptosomal-associated protein of 25 kDa (SNAP-25)-blocking peptide abolished DHPG-induced increases in NMDAR currents of PVN neurons in SHRs. Our findings suggest that mGluR5 in the PVN is upregulated in hypertension and contributes to the hyperactivity of PVN presympathetic neurons through PKC-and SNAP-25-mediated surface expression of NMDARs.

Microglia Participate in Neurogenic Regulation of Hypertension

“…To understand whether microglia affect neuronal plasticity in hypertension, we examined the expression of the N-methyl-D-aspartate (NMDA) receptor, an excitatory synaptic receptor reported to be critical for neurogenic hypertension 21 . In the hypertensive PVN, the expression of NMDA subunit GluN2A was up-regulated by 2 folds (Figure 4C).…”

“…A recent study shows that brain-derived neurotrophic factor (BDNF) produced by microglial are of importance in the regulation of neuronal activity by increasing the expression of NMDA receptors on the postsynaptic terminals 16 . Given the essential role of NMDA receptors in neuronal excitation and plasticity 21 , signals triggering NMDA receptor presentation are the key factors on neuronal activity. NMDA receptor is a tetrametric glutamate-gated ion channel, assembled by an essential subunit, NR1, and one or more components of a second family of subunits NR2A to D and NR3A/B 27 .…”

Vasopressin V1a receptors mediate the hypertensive effects of [Pyr1]apelin‐13 in the rat rostral ventrolateral medulla

“…) and glutamate (Li et al . ) receptors are upregulated in the RVLM of SHR, a model of essential hypertension that has an increased basal vasomotor tone. Thus, there may be a shift in the balance of inhibitory and excitatory inputs in SHR brain regions to produce variable physiological changes not seen in the normotensive state.…”

Redistribution of NMDA Receptors in Estrogen-Receptor-β-Containing Paraventricular Hypothalamic Neurons following Slow-Pressor Angiotensin II Hypertension in Female Mice with Accelerated Ovarian Failure

“…The hypothalamic paraventricular nucleus (PVN) receives a prominent glutamate input from the AngII-sensitive subfornical organ, and this circuit is crucial for the sympathoexcitation underlying slow-pressor AngII-induced hypertension [21–23]. In males, upregulation of postsynaptic N-methyl-D-aspartate (NMDA) receptor function in PVN neurons that project to the spinal cord may play a pivotal role in the enhanced excitatory drive seen in hypertension models [24–26]. Activated NMDA receptors can stimulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, generating reactive oxygen species (ROS), leading to the activation of voltage-gated L-type Ca 2+ currents [7, 27, 28] .…”