(R)-alpha-methylhistamine Suppresses Inhibitory Neurotransmission in Hippocampal CA1 Pyramidal Neurons Counteracting Propofol-Induced Amnesia in Rats
(R)-alpha-methylhistamine Suppresses Inhibitory Neurotransmission in Hippocampal CA1 Pyramidal Neurons Counteracting Propofol-Induced Amnesia in Rats
复制标题
(R)-α-甲基组胺抑制海马 CA1 锥体神经元的抑制性神经传递，抵消异丙酚引起的大鼠遗忘症
DOI：
10.1111/cns.12294
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发表时间：
2014-09-01
影响因子：
5.5
通讯作者：
Shi, Xue-Yin
中科院分区：
文献类型：
--
作者：
Li, Wei-Wei;Cheng, Long-Zhen;Shi, Xue-Yin
背景：异丙酚是一种短效静脉全身麻醉剂，在临床上广泛应用于短程序，但它会导致认知功能下降数小时。(R)-α-甲基组胺(RAMH)是一种选择性组胺H3受体激动剂，可增强大鼠的记忆保持能力，减轻记忆损害。在这项研究中，我们研究了RAMH是否可以修复异丙酚诱导的记忆障碍，以及参与这一过程的潜在机制。方法：在改良Morris水迷宫(MWM)实验中，大鼠随机分为对照组、异丙酚(25 mg/kg，训练前30min)、RAMH(10 mg/kg，训练前60min)和异丙酚+RAMH组。所有大鼠接受为期2天的训练，第3天进行探头测试。记录大鼠海马片CA1区神经元的场兴奋性突触后电位，并用电刺激(TBS)或高频强直刺激(HFS)诱导长时程增强(LTP)。用全细胞膜片钳记录CA1区锥体神经元的自发和微小抑制性(sIPSCs，mIPSCs)或兴奋性(sEPSCs，mEPSCs)突触后电流。结果：在MWM任务中，异丙酚注射显著损害空间记忆保持。RAMH可逆转异丙酚诱导的记忆保持。在海马CA1脑片上，异丙酚灌流显著抑制TBS诱导的LTP，但不抑制HFS诱导的LTP。联合灌流RAMH可逆转异丙酚对TBS诱导的LTP降低的抑制作用。此外，在海马CA1区锥体神经元中，RAMH显著抑制sIPSCs和mIPSCs的频率而不抑制其幅度，而对sEPSCs和mEPSCs的频率和幅度几乎没有影响。结论：RAMH通过抑制突触前GABA能神经传递，抑制了海马CA1区锥体神经元的抑制性神经传递，从而逆转了异丙酚对CA1LTP的抑制和大鼠的空间记忆障碍。
Background: Propofol is a short-acting, intravenous general anesthetic that is widely used in clinical practice for short procedures; however, it causes depressed cognitive function for several hours thereafter. (R)-alpha-methylhistamine (RAMH), a selective histamine H3 receptor agonist, can enhance memory retention and attenuates memory impairment in rats. In this study, we investigated whether RAMH could rescue propofol-induced memory deficits and the underlying mechanisms partaking in this process. Methods: In the modified Morris water maze (MWM) test, rats were randomized into the following groups: control, propofol (25 mg/kg, i.p., 30 min before training), RAMH (10 mg/kg, i.p., 60 min before training), and propofol plus RAMH. All randomized rats were subjected to 2 days of training, and a probe test was conducted on day 3. Field excitatory postsynaptic potentials were recorded from CA1 neurons in rat hippocampal slices, and long-term potentiation (LTP) was induced by either theta-burst stimulation (TBS) or high-frequency tetanic stimulation (HFS). Spontaneous and miniature inhibitory (sIPSCs, mIPSCs) or excitatory (sEPSCs, mEPSCs) postsynaptic currents were recorded from CA1 pyramidal neurons by whole-cell patch clamp. Results: In the MWM task, propofol injection significantly impaired spatial memory retention. Pretreatment with RAMH reversed propofol-induced memory retention. In hippocampal CA1 slices, propofol perfusion markedly inhibited TBS-but not HFS-induced LTP. Co-perfusion of RAMH reversed the inhibitory effect of propofol on TBS-induced LTP reduction. Furthermore, in hippocampal CA1 pyramidal neurons, RAMH significantly suppressed the frequency but not the amplitude of sIPSCs and mIPSCs and had little effects on both the frequency and amplitude of sEPSCs and mEPSCs. Conclusions: Our results suggest that RAMH, by inhibiting presynaptic GABAergic neurotransmission, suppresses inhibitory neurotransmission in hippocampal CA1 pyramidal neurons, which in turn reverses inhibition of CA1 LTP and the spatial memory deficits induced by propofol in rats.