Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Neuropharmacology. 2019 Nov 1;158:107710. doi: 10.1016/j.neuropharm.2019.107710. Epub 2019 Jul 13.
Recent studies have shown that ketamine, an open channel blocker of the N-methyl-d-aspartate receptor (NMDAR), is effective for patients with treatment-resistant depression. In this study, we aimed to elucidate the potential link between antidepressant-like effects of a single ketamine administration and dorsoventral differentiation in adult hippocampal neurogenesis. Immunohistochemical analyses revealed that elevation in the densities of neuronal progenitors and newborn granule cells by ketamine was seen in the ventral (related to emotion), but not dorsal (related to spatial memory), hippocampus in adult mice, although the densities of neural stem cells were not affected by ketamine in both the dorsal and ventral regions. Promotion of maturation of newborn granule cells by ketamine was evident in the ventral, but not dorsal, hippocampus. Behavioral analyses showed that ketamine did not affect spatial memory but ameliorated depression-related behavior. Western blot analyses showed that the basal expression of the GluN2B, but not GluN1, subunit of the NMDAR was higher in the ventral hippocampus than in the dorsal hippocampus. The induction of expression of GluN2B subunit of the NMDAR, phosphorylated mammalian target of rapamycin (p-mTOR), GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and brain derived neurotrophic factor (BDNF), by ketamine was greater in the ventral hippocampus than in the dorsal hippocampus. Our results demonstrate that a single ketamine administration promotes adult neurogenesis in the ventral hippocampus quite selectively. Furthermore, ventral-dominant induction of the GluN2B subunit of NMDAR, p-mTOR, GluA1 subunit of AMPAR, and BDNF, in the hippocampus may underlie the unique antidepressant-like effects of ketamine.
最近的研究表明，氯胺酮是一种 N-甲基-D-天冬氨酸受体（NMDAR）的开放通道阻断剂，对治疗抵抗性抑郁症患者有效。在这项研究中，我们旨在阐明单次氯胺酮给药的抗抑郁样效应与成年海马神经发生的背腹分化之间的潜在联系。免疫组织化学分析显示，氯胺酮增加了成年小鼠海马腹侧（与情绪有关）而非背侧（与空间记忆有关）神经元祖细胞和新生颗粒细胞的密度，尽管氯胺酮对背侧和腹侧区域的神经干细胞密度没有影响。氯胺酮促进新生颗粒细胞的成熟在海马腹侧而非背侧明显。行为分析表明，氯胺酮不影响空间记忆，但改善了与抑郁相关的行为。Western blot 分析显示，NMDAR 的 GluN2B 亚基（而不是 GluN1 亚基）的基础表达在海马腹侧高于背侧。NMDAR 的 GluN2B 亚基、磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的 GluA1 亚基和脑源性神经营养因子（BDNF）的表达在海马腹侧比背侧诱导更大。我们的结果表明，单次氯胺酮给药可选择性地促进成年海马神经发生。此外，海马中 NMDAR 的 GluN2B 亚基、p-mTOR、AMPAR 的 GluA1 亚基和 BDNF 的腹侧优势诱导可能是氯胺酮独特抗抑郁样作用的基础。
