Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.
Neuropharmacology. 2021 Dec 15;201:108833. doi: 10.1016/j.neuropharm.2021.108833. Epub 2021 Oct 9.
The GluN2 subunits of N-methyl-d-aspartate receptors (NMDARs) are key drivers of synaptic plasticity in the brain, where the particular GluN2 composition endows the NMDAR complex with distinct pharmacological and physiological properties. Compared to GluN2A and GluN2B subunits, far less is known about the role of the GluN2D subunit in synaptic plasticity. In this study, we have used a GluN2C/2D selective competitive antagonist, UBP145, in combination with a GluN2D global knockout (GluN2D KO) mouse line to study the contribution of GluN2D-containing NMDARs to short-term potentiation (STP) and long-term potentiation (LTP) in the CA1 region of mouse hippocampal slices. We made several distinct observations: First, GluN2D KO mice have higher levels of LTP compared to wild-type (WT) mice, an effect that was occluded by blockade of GABA receptor-mediated inhibition or by using a strong LTP induction protocol. Second, UBP145 partially inhibited LTP in WT but not GluN2D KO mice. Third, UBP145 inhibited a component of STP, termed STP2, in WT but not GluN2D KO mice. Taken together, these findings suggest an involvement for GluN2D-containing NMDARs in both STP and LTP in mouse hippocampus.
N-甲基-D-天冬氨酸受体（NMDAR）的 GluN2 亚基是大脑中突触可塑性的关键驱动因素，其中特定的 GluN2 组成赋予 NMDAR 复合物独特的药理学和生理学特性。与 GluN2A 和 GluN2B 亚基相比，人们对 GluN2D 亚基在突触可塑性中的作用知之甚少。在这项研究中，我们使用 GluN2C/2D 选择性竞争性拮抗剂 UBP145，结合 GluN2D 全局敲除（GluN2D KO）小鼠系，研究 GluN2D 包含的 NMDAR 对 CA1 区小鼠海马切片中短期增强（STP）和长期增强（LTP）的贡献。我们有几个不同的观察结果：首先，与野生型（WT）小鼠相比，GluN2D KO 小鼠的 LTP 水平更高，这种效应被 GABA 受体介导的抑制阻断或使用强 LTP 诱导方案所掩盖。其次，UBP145 部分抑制 WT 小鼠的 LTP，但不抑制 GluN2D KO 小鼠的 LTP。第三，UBP145 抑制 WT 小鼠的 STP 成分，称为 STP2，但不抑制 GluN2D KO 小鼠的 STP2。总之，这些发现表明 GluN2D 包含的 NMDAR 参与了小鼠海马体中的 STP 和 LTP。
