High Salt Intake Recruits Tonic Activation of NR2D Subunit-Containing Extrasynaptic NMDARs in Vasopressin Neurons

Abstract

In addition to producing a classical excitatory postsynaptic current via activation of synaptic NMDA receptors (NMDARs), glutamate in the brain also induces a tonic NMDAR current (I NMDA ) via activation of extrasynaptic NMDARs (eNMDARs). However, since Mg 21 blocks NMDARs in nondepolarized neurons, the potential contribution of eNMDARs to the overall neuronal excitatory/inhibitory (E/I) balance remains unknown. Here, we demonstrate that chronic (7 d) salt loading (SL) recruited NR2D subunitcontaining NMDARs to generate an Mg 21 -resistant tonic I NMDA in nondepolarized [V h (holding potential) 270 mV] vasopressin (VP; but not oxytocin) supraoptic nucleus (SON) neurons in male rodents. Conversely, in euhydrated (EU) and 3 d SL mice, Mg 21 -resistant tonic I NMDA was not observed. Pharmacological and genetic intervention of NR2D subunits blocked the Mg 21resistant tonic I NMDA in VP neurons under SL conditions, while an NR2B antagonist unveiled Mg 21 -sensitive tonic I NMDA but not Mg 21 -resistant tonic I NMDA . In the EU group VP neurons, an Mg 21 -resistant tonic I NMDA was not generated by increased ambient glutamate or treatment with coagonists (e.g., D-serine and glycine). Chronic SL significantly increased NR2D expression but not NR2B expression in the SON relative to the EU group or after 3 d under SL conditions. Finally, Mg 21 -resistant tonic I NMDA selectively upregulated neuronal excitability in VP neurons under SL conditions, independent of ionotropic GABAergic input. Our results indicate that the activation of NR2D-containing NMDARs constitutes a novel mechanism that generates an Mg 21 -resistant tonic I NMDA in nondepolarized VP neurons, thus causing an E/I balance shift in VP neurons to compensate for the hormonal demands imposed by a chronic osmotic challenge.

Cerebral organoids transplantation repairs infarcted cortex and restores impaired function after stroke

“…4e ) and found that the illumination resulted in inward currents in GFP + neurons under voltage-clamp recording conditions at a holding potential of −65 mV (Fig. 4f ) and the PSCs were blocked by the application of ionotropic glutamate receptor antagonist kynurenic acid 35 (Fig. 4g ), suggesting a glutaminergic synaptic afferent from host neurons to the neurons of grafted organoids.…”

NMDA Receptors in the Lateral Preoptic Hypothalamus Are Essential for Sustaining NREM and REM Sleep

“…But these same properties also allow NMDA receptors to act as pacemakers, controlling rhythmic firing, e.g., in those circuits involved in breathing, swimming, and walking (Steenland et al, 2008;Li et al, 2010), as well as contributing to the generation of burst firing of reticular thalamic neurons (Deleuze and Huguenard, 2016). The long open times of NMDA receptors, especially those located extrasynaptically, could be contributing to tonic excitation (Sah et al, 1989;Neupane et al, 2021), stabilizing hypothalamic sleep-on neurons in their firing mode. It will be interesting to see whether this role of NMDA receptors generalizes to other sleep-promoting circuits.…”

“…One critical factor maintaining sleep could be NMDA-type glutamate receptors. These channels, especially when located extrasynaptically, can provide tonic excitation (Sah et al, 1989;Papouin et al, 2012;Neupane et al, 2021). Indeed, NMDA receptor activation promotes sleep.…”

MAO-B Inhibitor, KDS2010, Alleviates Spinal Nerve Ligation-induced Neuropathic Pain in Rats Through Competitively Blocking the BDNF/TrkB/NR2B Signaling

“…The NMDA receptor-mediated tonic current was estimated by holding current difference before and after the application of NMDA receptors antagonists; ifenprodil (IFN; 30 μM, Tocris) and DL-2-Amino-5-phosphonopentanoic acid (DL-AP5; 100 μM, Tocris) as in our previous reports 41 .…”