Allosteric Modulation of Related Ligand-Gated Ion Channels Synergistically Induces Long-Term Potentiation in the Hippocampus and Enhances Cognition
Allosteric Modulation of Related Ligand-Gated Ion Channels Synergistically Induces Long-Term Potentiation in the Hippocampus and Enhances Cognition
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DOI：
10.1124/jpet.110.176255
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发表时间：
2011-03-01
影响因子：
3.5
通讯作者：
Gee, Kelvin W.
中科院分区：
文献类型：
--
作者：
Johnstone, Timothy B.;Gu, Zhenglin;Gee, Kelvin W.
含α5亚单位的GABA(A)受体(GABA(A)Rs)和α7神经元尼古丁-乙酰胆碱受体(NAChRs)是配体门控离子通道(LGIC)Cys环家族的成员，在海马区介导认知和注意过程。α-5-GABA(A)受体通过紧张性抑制海马区CA1/CA3锥体细胞而改变网络活动。突触后α7 nAChRs调节CA1区锥体神经元同步化所需的抑制性GABA能中间神经元活性，而突触前α7 nAChRs调节谷氨酸释放。这些LGIC的同时变构调节能否在认知上产生协同效应？我们发现，联合应用两种变构调节剂，分别1)抑制α5-GABA(A)受体和2)增强α-7-nAChRs，可引起苔藓纤维刺激诱导的大鼠海马片CA1锥体神经元兴奋性突触后电流(EPSC)的长期增强(LTP)。我们设计的一种同时抑制α5-GABA(A)受体和增强α7 nAChRs的化合物3-(2，5-difluorophenyl)-6-(N-ethylindol-5-yl)-1，2，4-triazolo[4，3-b]哒嗪(522-054)复制了两种化合物引起的LTP效应。选择性拮抗剂可阻断522-054产生的EPSC增强效应。在体内，522-054提高了在放射臂迷宫中的表现，并在具有相似受体拮抗剂敏感性的五个选择的系列反应时间试验中促进了注意力状态。这些观察结果可能转化为双重作用化合物对基于海马体的认知障碍疾病的治疗作用。
alpha 5 Subunit-containing GABA(A) receptors (GABA(A)Rs) and alpha 7 neuronal nicotinic-acetylcholine receptors (nAChRs) are members of the Cys-loop family of ligand-gated ion channels (LGICs) that mediate cognitive and attentional processes in the hippocampus. alpha 5 GABA(A)Rs alter network activity by tonic inhibition of CA1/CA3 pyramidal cells of the hippocampus. Postsynaptic alpha 7 nAChRs in the hippocampus regulate inhibitory GABAergic interneuron activity required for synchronization of pyramidal neurons in the CA1, whereas presynaptic alpha 7 nAChRs regulate glutamate release. Can simultaneous allosteric modulation of these LGICs produce synergistic effects on cognition? We show that combined transient application of two allosteric modulators that individually 1) inhibit alpha 5 GABA(A)Rs and 2) enhance alpha 7 nAChRs causes long-term potentiation (LTP) of mossy fiber stimulation-induced excitatory postsynaptic currents (EPSC) from CA1 pyramidal neurons of rat hippocampal slices. The LTP effect evoked by two compounds is replicated by 3-(2,5-difluorophenyl)-6-(N-ethylindol-5-yl)-1,2,4-triazolo[4,3-b] pyridazine (522-054), a compound we designed to simultaneously inhibit alpha 5 GABA(A)Rs and enhance alpha 7 nAChRs. Selective antagonists for either receptor block sustained EPSC potentiation produced by 522-054. In vivo, 522-054 enhances performance in the radial arm maze and facilitates attentional states in the five-choice serial reaction time trial with similar receptor antagonist sensitivity. These observations may translate into therapeutic utility of dual action compounds in diseases of hippocampal-based cognitive impairment.