PMID- 33303677 OWN - NLM STAT- MEDLINE DCOM- 20210427 LR - 20210811 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 41 IP - 6 DP - 2021 Feb 10 TI - High Salt Intake Recruits Tonic Activation of NR2D Subunit-Containing Extrasynaptic NMDARs in Vasopressin Neurons. PG - 1145-1156 LID - 10.1523/JNEUROSCI.1742-20.2020 [doi] AB - 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(2+) 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 subunit-containing NMDARs to generate an Mg(2+)-resistant tonic I(NMDA) in nondepolarized [V(h) (holding potential) -70 mV] vasopressin (VP; but not oxytocin) supraoptic nucleus (SON) neurons in male rodents. Conversely, in euhydrated (EU) and 3 d SL mice, Mg(2+)-resistant tonic I(NMDA) was not observed. Pharmacological and genetic intervention of NR2D subunits blocked the Mg(2+)-resistant tonic I(NMDA) in VP neurons under SL conditions, while an NR2B antagonist unveiled Mg(2+)-sensitive tonic I(NMDA) but not Mg(2+)-resistant tonic I(NMDA) In the EU group VP neurons, an Mg(2+)-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(2+)-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(2+)-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.SIGNIFICANCE STATEMENT The hypothalamic supraoptic nucleus (SON) consists of two different types of magnocellular neurosecretory cells (MNCs) that synthesize and release the following two peptide hormones: vasopressin (VP), which is necessary for regulation of fluid homeostasis; and oxytocin (OT), which plays a major role in lactation and parturition. NMDA receptors (NMDARs) play important roles in shaping neuronal firing patterns and hormone release from the SON MNCs in response to various physiological challenges. Our results show that prolonged (7 d) salt loading generated a Mg(2+)-resistant tonic NMDA current mediated by NR2D subunit-containing receptors, which efficiently activated nondepolarized VP (but not OT) neurons. Our findings support the hypothesis that NR2D subunit-containing NMDARs play an important adaptive role in adult brain in response to a sustained osmotic challenge. CI - Copyright (c) 2021 the authors. FAU - Neupane, Chiranjivi AU - Neupane C AUID- ORCID: 0000-0003-2719-9331 AD - Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea. AD - Biomedicine, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea. FAU - Sharma, Ramesh AU - Sharma R AD - Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea. AD - Biomedicine, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea. FAU - Pai, Yoon Hyung AU - Pai YH AD - Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea. FAU - Lee, So Yeong AU - Lee SY AD - Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea. FAU - Jeon, Byeong Hwa AU - Jeon BH AD - Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea. AD - Biomedicine, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea. FAU - Kim, Hyun-Woo AU - Kim HW AD - Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea. AD - Biomedicine, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea. FAU - Stern, Javier E AU - Stern JE AD - Neuroscience Institute, Georgia State University, Atlanta, Georgia 30302. FAU - Park, Jin Bong AU - Park JB AD - Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea jinbong@cnu.ac.kr. AD - Biomedicine, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea. LA - eng GR - R01 NS094640/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201210 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (NR2D NMDA receptor) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Sodium Chloride, Dietary) RN - 11000-17-2 (Vasopressins) SB - IM MH - Animals MH - Excitatory Amino Acid Antagonists/pharmacology MH - Excitatory Postsynaptic Potentials/drug effects/physiology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neurons/drug effects/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Rats, Transgenic MH - Rats, Wistar MH - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/*metabolism MH - Sodium Chloride, Dietary/*administration & dosage MH - Synapses/drug effects/*metabolism MH - Vasopressins/*metabolism PMC - PMC7888215 OTO - NOTNLM OT - NR2D OT - iMK801 OT - oxytocin OT - salt loading OT - tonic NMDA OT - vasopressin EDAT- 2020/12/12 06:00 MHDA- 2021/04/28 06:00 PMCR- 2021/08/10 CRDT- 2020/12/11 05:51 PHST- 2020/07/06 00:00 [received] PHST- 2020/11/19 00:00 [revised] PHST- 2020/11/25 00:00 [accepted] PHST- 2020/12/12 06:00 [pubmed] PHST- 2021/04/28 06:00 [medline] PHST- 2020/12/11 05:51 [entrez] PHST- 2021/08/10 00:00 [pmc-release] AID - JNEUROSCI.1742-20.2020 [pii] AID - JN-RM-1742-20 [pii] AID - 10.1523/JNEUROSCI.1742-20.2020 [doi] PST - ppublish SO - J Neurosci. 2021 Feb 10;41(6):1145-1156. doi: 10.1523/JNEUROSCI.1742-20.2020. Epub 2020 Dec 10.