Wu Min, Hajszan Tibor, Xu Changqing, Leranth Csaba, Alreja Meenakshi
Dept. of Psychiatry, CMHC 335A, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508.
J Neurophysiol. 2004 Aug;92(2):1216-25. doi: 10.1152/jn.00180.2004. Epub 2004 Mar 24.
Septohippocampal cholinergic neurons innervate the hippocampus and provide it with almost its entire acetylcholine. Axon collaterals of these neurons also release acetylcholine within the septum and thereby maintain the firing activity of septohippocampal GABAergic neurons. A loss of septohippocampal cholinergic neurons occurs in various neurodegenerative disorders associated with cognitive dysfunctions. group I metabotropic glutamate receptors have been implicated in septohippocampal-dependent learning and memory tasks. In the present study, we examined the physiological and pharmacological effects of a potent and selective group I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydroxyphenylglycine (DHPG) on rat septohippocampal cholinergic neurons that were identified in brain slices using a selective fluorescent marker. In whole cell recordings, DHPG produced a reversible, reproducible and a direct postsynaptic and concentration-dependent excitation in 100% of septohippocampal cholinergic neurons tested with an EC(50) of 2.1 microM. Pharmacologically, the effects of DHPG were partially/completely reduced by the mGluR1 antagonists, 7-hydrox-iminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester and (+)-2-methyl-4-carboxyphenylglycine. Addition of the mGluR5 antagonist, 2-methyl-6-(phenylethnyl)pyridine hydrochloride, reduced the remaining response to DHPG, suggesting involvement of both receptor subtypes in a subpopulation of septohippocampal cholinergic neurons. In double-immunolabeling studies, 74% of septohippocampal cholinergic neurons co-localized mGluR1alpha-immunoreactivity and 35% co-localized mGluR5-immunoreactivity. Double-immunolabeling studies at the light and electron-microscopic levels showed that vesicular glutamate transporter 2 terminals make asymmetric synaptic contacts with septohippocampal cholinergic neurons. These findings may be of significance in treatment of cognitive deficits associated with neurodegenerative disorders as a group I mGluR-mediated activation of septohippocampal cholinergic neurons would enhance the release of acetylcholine both in the hippocampus and in the septum.
隔海马胆碱能神经元支配海马，并为其提供几乎全部的乙酰胆碱。这些神经元的轴突侧支也在隔区内释放乙酰胆碱，从而维持隔海马GABA能神经元的放电活动。在与认知功能障碍相关的各种神经退行性疾病中，隔海马胆碱能神经元会发生缺失。I组代谢型谷氨酸受体与依赖隔海马的学习和记忆任务有关。在本研究中，我们使用选择性荧光标记物在脑片中鉴定了大鼠隔海马胆碱能神经元，研究了一种强效且选择性的I组代谢型谷氨酸受体（mGluR）激动剂S-3,5-二羟基苯甘氨酸（DHPG）对这些神经元的生理和药理作用。在全细胞记录中，DHPG在100%的受试隔海马胆碱能神经元中产生了可逆、可重复且直接的突触后浓度依赖性兴奋，其半数有效浓度（EC50）为2.1微摩尔。从药理学角度来看，mGluR1拮抗剂7-羟基-亚氨基环丙烷[b]色烯-1a-羧酸乙酯和（+）-2-甲基-4-羧基苯甘氨酸可部分/完全降低DHPG的作用。添加mGluR5拮抗剂盐酸2-甲基-6-（苯乙炔基）吡啶可降低对DHPG的剩余反应，表明这两种受体亚型均参与了隔海马胆碱能神经元亚群的活动。在双重免疫标记研究中，74%的隔海马胆碱能神经元共定位有mGluR1α免疫反应性，35%共定位有mGluR5免疫反应性。光镜和电镜水平的双重免疫标记研究表明，囊泡谷氨酸转运体2终末与隔海马胆碱能神经元形成不对称突触联系。这些发现对于治疗与神经退行性疾病相关的认知缺陷可能具有重要意义，因为I组mGluR介导的隔海马胆碱能神经元激活会增强海马和隔区内乙酰胆碱的释放。
