Bærentzen Simone Larsen, Waszkiewicz Anna Lee, Thomsen Majken, Knudsen Celine, Elfving Betina, Landau Anne M
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Neurosci Appl. 2024 Jun 20;3:104079. doi: 10.1016/j.nsa.2024.104079. eCollection 2024.
The N-methyl-D-aspartate receptor (NMDA-R) antagonist S-ketamine has been approved as a rapid-acting antidepressant for treatment-resistant depression (TRD). The antidepressant mechanisms have not fully been elucidated; however, alterations of synaptic proteins and mechanisms may play a vital role. Here, we study the effect of a single subanaesthetic dose of 15 mg/kg S-ketamine vs saline 1 h after administration in the Wistar Kyoto rat model of depression on the density of synaptic vesicle glycoprotein 2A (SV2A) and the metabotropic glutamate receptor 5 (mGluR5) using [H]UCB-J and [H]MPEPγ autoradiography, respectively, compared with control Wistar Hannover rats. In a separate cohort of Wistar Kyoto rats, we investigate the transcriptional regulation of presynaptic markers , , postsynaptic markers , NMDA receptor subunits , AMPA receptor subunits , GABA type A receptor-associated protein (), glutamate metabotropic receptor subtype 5 (), and brain-derived neurotrophic factor () using real-time quantitative polymerase chain reaction (qPCR) in hippocampus in response to S-ketamine vs saline injection. In Wistar Kyoto rats, S-ketamine increases [H]UCB-J binding to SV2A compared to saline-injected controls in the nucleus accumbens and dorsal and ventral hippocampus, an effect absent in the Wistar Hannover strain. No changes were observed in [H]MPEPγ binding to mGluR5, nor in gene regulation. S-ketamine can regulate presynaptic SV2A density in brain areas relevant to depression in the Wistar Kyoto model, but not in controls, suggesting a role for SV2A in the antidepressant effects of S-ketamine.
N-甲基-D-天冬氨酸受体（NMDA-R）拮抗剂S-氯胺酮已被批准作为一种速效抗抑郁药用于治疗难治性抑郁症（TRD）。其抗抑郁机制尚未完全阐明；然而，突触蛋白和机制的改变可能起着至关重要的作用。在此，我们在Wistar Kyoto抑郁大鼠模型中，于给药1小时后，研究单次亚麻醉剂量15mg/kg的S-氯胺酮与生理盐水相比，分别使用[H]UCB-J和[H]MPEPγ放射自显影术对突触囊泡糖蛋白2A（SV2A）和代谢型谷氨酸受体5（mGluR5）密度的影响，并与对照Wistar Hannover大鼠进行比较。在另一组Wistar Kyoto大鼠中，我们使用实时定量聚合酶链反应（qPCR）研究海马体中突触前标志物、突触后标志物、NMDA受体亚基、AMPA受体亚基、GABA A型受体相关蛋白（）、谷氨酸代谢型受体亚型5（）和脑源性神经营养因子（）对S-氯胺酮与生理盐水注射的转录调控。在Wistar Kyoto大鼠中，与注射生理盐水的对照组相比，S-氯胺酮增加了伏隔核、背侧和腹侧海马体中[H]UCB-J与SV2A的结合，而Wistar Hannover品系中未观察到这种效应。[H]MPEPγ与mGluR5的结合以及基因调控均未观察到变化。在Wistar Kyoto模型中，S-氯胺酮可调节与抑郁相关脑区的突触前SV2A密度，但对照组中未出现这种情况，这表明SV2A在S-氯胺酮的抗抑郁作用中发挥了作用。
