Department of Physiology, Chungnam National University, Daejeon 35015, Republic of Korea.
Biomedicine, Brain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea.
J Neurosci. 2021 Feb 10;41(6):1145-1156. doi: 10.1523/JNEUROSCI.1742-20.2020. Epub 2020 Dec 10.
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 () via activation of extrasynaptic NMDARs (eNMDARs). However, since Mg 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-resistant tonic in nondepolarized [ (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-resistant tonic was not observed. Pharmacological and genetic intervention of NR2D subunits blocked the Mg-resistant tonic in VP neurons under SL conditions, while an NR2B antagonist unveiled Mg-sensitive tonic but not Mg-resistant tonic In the EU group VP neurons, an Mg-resistant tonic 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-resistant tonic 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-resistant tonic 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. 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-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.
除了通过激活突触 NMDA 受体 (NMDAR) 产生经典的兴奋性突触后电流外，大脑中的谷氨酸还通过激活 extrasynaptic NMDARs (eNMDARs) 诱导持续的 NMDAR 电流 ()。然而，由于 Mg 阻断未去极化神经元中的 NMDAR，因此 eNMDAR 对整体神经元兴奋/抑制 (E/I) 平衡的潜在贡献仍然未知。在这里，我们证明慢性（7 d）盐负荷（SL）募集 NR2D 亚基包含的 NMDAR 以产生持续的 在未去极化的 [（保持电位）-70 mV] 血管加压素（VP；但不是催产素）视上核（SON）神经元中在雄性啮齿动物中。相反，在正常水合（EU）和 3 d SL 小鼠中，未观察到 Mg 抗性持续 。在 SL 条件下，NR2D 亚基的药理学和遗传学干预阻断了 VP 神经元中的 Mg 抗性持续 ，而 NR2B 拮抗剂揭示了 Mg 敏感的持续 但不是 Mg 抗性的持续 在 EU 组 VP 神经元中，增加的细胞外谷氨酸或用共激动剂（例如 D-丝氨酸和甘氨酸）处理不会产生 Mg 抗性的持续 。慢性 SL 显著增加了 SON 中 NR2D 的表达，但相对于 EU 组或在 SL 条件下 3 d 后，NR2B 的表达没有增加。最后，Mg 抗性持续 在 SL 条件下选择性地上调 VP 神经元的神经元兴奋性，而与离子型 GABA 能输入无关。我们的结果表明，NR2D 包含的 NMDAR 的激活构成了一种新的机制，可在未去极化的 VP 神经元中产生 Mg 抗性持续 ，从而导致 VP 神经元中的 E/I 平衡转移，以补偿由慢性渗透挑战引起的激素需求。下丘脑视上核（SON）由两种不同类型的大细胞神经分泌细胞（MNC）组成，它们合成并释放以下两种肽激素：血管加压素（VP），这对于调节体液平衡是必需的；和催产素（OT），它在泌乳和分娩中起主要作用。NMDA 受体（NMDAR）在响应各种生理挑战时，在塑造 SON MNC 中的神经元发射模式和激素释放方面发挥重要作用。我们的结果表明，长期（7 d）盐负荷产生了由 NR2D 亚基包含的受体介导的 Mg 抗性持续 NMDA 电流，该电流有效地激活了未去极化的 VP（但不是 OT）神经元。我们的发现支持这样的假设，即 NR2D 亚基包含的 NMDAR 在应对持续的渗透挑战时在成年大脑中发挥重要的适应性作用。
