Department of Anesthesiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
CNS Neurosci Ther. 2014 Sep;20(9):851-9. doi: 10.1111/cns.12294. Epub 2014 Jun 20.
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.
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.
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.
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.
丙泊酚是一种短效的静脉全身麻醉药，广泛用于临床的短程手术；但此后数小时会引起认知功能下降。（R）-α-甲基组氨酸（RAMH），一种选择性组胺 H3 受体激动剂，可增强记忆保留并减轻大鼠的记忆障碍。在这项研究中，我们研究了 RAMH 是否可以挽救丙泊酚引起的记忆缺陷，以及参与该过程的潜在机制。
在改良的 Morris 水迷宫（MWM）测试中，大鼠被随机分为以下几组：对照组、丙泊酚（25mg/kg，腹腔注射，训练前 30 分钟）、RAMH（10mg/kg，腹腔注射，训练前 60 分钟）和丙泊酚加 RAMH。所有随机分组的大鼠均进行 2 天的训练，并在第 3 天进行探针测试。记录大鼠海马切片 CA1 神经元的场兴奋性突触后电位，通过 theta 爆发刺激（TBS）或高频强直刺激（HFS）诱导长时程增强（LTP）。通过全细胞膜片钳记录 CA1 锥体神经元的自发性和微小抑制性（sIPSCs、mIPSCs）或兴奋性（sEPSCs、mEPSCs）突触后电流。
在 MWM 任务中，丙泊酚注射显著损害空间记忆保留。RAMH 的预处理逆转了丙泊酚引起的记忆保留。在海马 CA1 切片中，丙泊酚灌流显著抑制 TBS 诱导但不抑制 HFS 诱导的 LTP。RAMH 共灌流逆转了丙泊酚对 TBS 诱导的 LTP 降低的抑制作用。此外，在海马 CA1 锥体神经元中，RAMH 显著抑制 sIPSCs 和 mIPSCs 的频率但不影响其幅度，对 sEPSCs 和 mEPSCs 的频率和幅度几乎没有影响。
我们的结果表明，RAMH 通过抑制突触前 GABA 能神经传递，抑制海马 CA1 锥体神经元的抑制性神经传递，从而逆转丙泊酚诱导的大鼠 CA1 LTP 抑制和空间记忆缺陷。
