Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression
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DOI：
10.1186/s13041-020-00627-z
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发表时间：
2020-06-16
期刊：
影响因子：
3.6
通讯作者：
Phillips, Anthony G.
中科院分区：
文献类型：
--
作者：
Aleksandrova, Lily R.;Wang, Yu Tian;Phillips, Anthony G.
越来越多的证据表明，在抑郁症的病理生理学中，海马区突触可塑性调节失调。然而，氯胺酮对突触可塑性的影响及其作为抗抑郁药的作用机制仍不清楚。在Wistar-京都(WKY)抑郁模型中，我们研究了氯胺酮对体内背侧海马区(DHPC)突触可塑性的影响以及它们在调节抗抑郁活性方面的作用。与Wistar对照组相比，WKY大鼠的dHPC长时程增强(LTP)显著受损。重要的是，单次小剂量(5 mg/kg，ip)氯胺酮或其代谢物(2R，6R)-HNK可在注射后3.5h挽救WKY大鼠LTP缺失，但不能在注射后30min恢复，但在24h仍有残留效应，表明对dHPC突触可塑性有延迟的、持续的易化作用。与观察到的dHPC LTP缺陷一致，WKY大鼠表现出新的物体位置识别测试(NOLRT)测量的海马区依赖长期空间记忆受损，该测试可通过氯胺酮或(2R，6R)-HNK预先处理有效地恢复。相比之下，在表现出异常应激应对的WKYS中，氯胺酮，而不是(2R，6R)-HNK，在强迫游泳试验(FST)中有快速和持久的效果，FST是一种常用的抗抑郁药样活动的临床前筛查。本文观察到的(2R，6R)-HNK的不同效应揭示了药物对FST不动和dHPC突触可塑性的分离作用。因此，在WKY大鼠模型中，恢复dHPC LTP与氯胺酮对FST的影响没有相关性，但重要的是，可能有助于逆转海马区依赖的认知障碍，这是临床抑郁症的关键特征。我们的发现支持这样一种理论，即氯胺酮可能通过参与突触可塑性过程来“重置系统”，从而逆转应激导致的关键神经回路连接的丧失。
Accumulating evidence implicates dysregulation of hippocampal synaptic plasticity in the pathophysiology of depression. However, the effects of ketamine on synaptic plasticity and their contribution to its mechanism of action as an antidepressant, are still unclear. We investigated ketamine's effects on in vivo dorsal hippocampal (dHPC) synaptic plasticity and their role in mediating aspects of antidepressant activity in the Wistar-Kyoto (WKY) model of depression. dHPC long-term potentiation (LTP) was significantly impaired in WKY rats compared to Wistar controls. Importantly, a single low dose (5 mg/kg, ip) of ketamine or its metabolite, (2R,6R)-HNK, rescued the LTP deficit in WKY rats at 3.5 h but not 30 min following injection, with residual effects at 24 h, indicating a delayed, sustained facilitatory effect on dHPC synaptic plasticity. Consistent with the observed dHPC LTP deficit, WKY rats exhibited impaired hippocampal-dependent long-term spatial memory as measured by the novel object location recognition test (NOLRT), which was effectively restored by pre-treatment with both ketamine or (2R,6R)-HNK. In contrast, in WKYs, which display abnormal stress coping, ketamine, but not (2R,6R)-HNK, had rapid and sustained effects in the forced swim test (FST), a commonly used preclinical screen for antidepressant-like activity. The differential effects of (2R,6R)-HNK observed here reveal a dissociation between drug effects on FST immobility and dHPC synaptic plasticity. Therefore, in the WKY rat model, restoring dHPC LTP was not correlated with ketamine's effects in FST, but importantly, may have contributed to the reversal of hippocampal-dependent cognitive deficits, which are critical features of clinical depression. Our findings support the theory that ketamine may reverse the stress-induced loss of connectivity in key neural circuits by engaging synaptic plasticity processes to "reset the system".