Sex differences in NMDA GluN1 plasticity in rostral ventrolateral medulla neurons containing corticotropin-releasing factor type 1 receptor following slow-pressor angiotensin II hypertension

Abstract

There are profound, yet incompletely understood, sex differences in the neurogenic regulation of blood pressure. Both corticotrophin signaling and glutamate receptor plasticity, which differ between males and females, are known to play important roles in the neural regulation of blood pressure. However, the relationship between hypertension and glutamate plasticity in corticotrophin-releasing hormone (CRF) receptive neurons in brain cardiovascular regulatory areas, including the rostral ventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN), is not understood. In the present study, we used dual label immunoelectron microscopy to analyze sex differences in slow-pressor angiotensin II (AngII) hypertension with respect to the subcellular distribution of the obligatory GluN1 subunit of the N-methyl-D-aspartate receptor (NMDAR) in the RVLM and PVN. Studies were conducted in mice expressing the enhanced green fluorescence protein (EGFP) under the control of the CRF type 1 receptor (CRF1) promoter (i.e., CRF1-EGFP reporter mice). By light microscopy, GluN1-immunoreactivity was found in CRF1-EGFP neurons of the RVLM and PVN. Moreover, in both regions tyrosine hydroxylase was found in CRF1-EGFP neurons. In response to AngII, male mice showed an elevation in blood pressure that was associated with an increase in the proportion of GluN1 on presumably functional areas of the plasma membrane in CRF1-EGFP dendritic profiles in the RVLM. In female mice, AngII was neither associated with an increase in blood pressure nor an increase in plasma membrane GluN1 in the RVLM. Unlike the RVLM, AngII-mediated hypertension had no effect on GluN1 localization in CRF1-EGFP dendrites in the PVN of either male or female mice. These studies provide an anatomical mechanism for sex-differences in the convergent modulation of RVLM catecholaminergic neurons by CRF and glutamate. Moreover, these results suggest that sexual dimorphism in AngII-induced hypertension is reflected by NMDA receptor trafficking in presumptive sympathoexcitatory neurons in the RVLM.

Understanding the broad influence of sex hormones and sex differences in the brain

“…Importantly, spatiotemporal deletion of the obligatory GluN1 subunit of the NMDA receptor in the PVN attenuates hypertension in males (Glass et al 2015). Our recent electron microscopy studies (Marques-Lopes et al 2015a, Marques-Lopes et al 2015b, Van Kempen et al 2015a) revealed that alterations in the subcellular distributions of GluN1 in ERβ-containing PVN neurons (but not those containing angiotensin type A receptors or CRF1 receptors (Marques-Lopes et al 2015a, Van Kempen et al 2015a) reflect the hypertensive responses of male and female mice following slow-pressor AngII. In particular, the density of GluN1 is elevated in hypertensive male and aged female mice but decreased in non-hypertensive young females (Marques-Lopes et al 2014).…”

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 emergence of hypertension in males, as well as in aging models of menopause, has been associated with glutamate-dependent plasticity in the hypothalamus [8, 9, 18–20]. 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].…”

Sex, the brain and hypertension: brain oestrogen receptors and high blood pressure risk factors

“…Using electron microscopy and immunolabelling in males, female rats in pro-oestrus and female rats in di-oestrus, the females were found to have more AT1 labelling in the dendrites of the RVLM compared with males, but less NADPH oxidase p47 subunit labelling [48]. In addition to the sex differences in ROS signalling in the RVLM, there are also suggestions that there are important sex differences in RVLM neurotransmission [50]. Glutamate neurotransmission and activation of the N-methyl-Daspartate (NMDA) receptor within the RVLM is known to be important in RVLM modulation of BP [50].…”

“…In addition to the sex differences in ROS signalling in the RVLM, there are also suggestions that there are important sex differences in RVLM neurotransmission [50]. Glutamate neurotransmission and activation of the N-methyl-Daspartate (NMDA) receptor within the RVLM is known to be important in RVLM modulation of BP [50]. Changes in the subcellular trafficking of the glutamate-receptor subunit 1 (GluN1) of the NMDA receptor is related to increases in both RVLM activity and SNA [50].…”

“…Glutamate neurotransmission and activation of the N-methyl-Daspartate (NMDA) receptor within the RVLM is known to be important in RVLM modulation of BP [50]. Changes in the subcellular trafficking of the glutamate-receptor subunit 1 (GluN1) of the NMDA receptor is related to increases in both RVLM activity and SNA [50]. Recent studies have shown that a low-dose infusion of AngII which increases blood pressure in males also results in an increase in trafficking of GluN1 in RVLM neurons of males but not females.…”