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High Salt Intake Recruits Tonic Activation of NR2D Subunit-Containing Extrasynaptic NMDARs in Vasopressin Neurons.
Neupane, Chiranjivi; Sharma, Ramesh; Pai, Yoon Hyung; Lee, So Yeong; Jeon, Byeong Hwa; Kim, Hyun-Woo; Stern, Javier E; Park, Jin Bong.
Afiliação
  • Neupane C; Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea.
  • Sharma R; Biomedicine, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
  • Pai YH; Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea.
  • Lee SY; Biomedicine, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
  • Jeon BH; Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea.
  • Kim HW; Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea.
  • Stern JE; Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea.
  • Park JB; Biomedicine, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
J Neurosci ; 41(6): 1145-1156, 2021 02 10.
Article em En | MEDLINE | ID: mdl-33303677
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 (INMDA) via activation of extrasynaptic NMDARs (eNMDARs). However, since Mg2+ 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 Mg2+-resistant tonic INMDA in nondepolarized [Vh (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, Mg2+-resistant tonic INMDA was not observed. Pharmacological and genetic intervention of NR2D subunits blocked the Mg2+-resistant tonic INMDA in VP neurons under SL conditions, while an NR2B antagonist unveiled Mg2+-sensitive tonic INMDA but not Mg2+-resistant tonic INMDA In the EU group VP neurons, an Mg2+-resistant tonic INMDA 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, Mg2+-resistant tonic INMDA 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 Mg2+-resistant tonic INMDA 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 Mg2+-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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article