Du Jing, Creson Thomas K, Wu Long-Jun, Ren Ming, Gray Neil A, Falke Cynthia, Wei Yanling, Wang Yun, Blumenthal Rayah, Machado-Vieira Rodrigo, Yuan Peixiong, Chen Guang, Zhuo Min, Manji Husseini K
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20878, USA.
J Neurosci. 2008 Jan 2;28(1):68-79. doi: 10.1523/JNEUROSCI.3080-07.2008.
The cellular basis underlying the complex clinical symptomatology of bipolar disorder and the mechanisms underlying the actions of its effective treatments have not yet been fully elucidated. This study investigated the role of hippocampal synaptic AMPA receptors. We found that chronic administration of the antimanic agents lithium and valproate (VPA) reduced synaptic AMPA receptor GluR1/2 in hippocampal neurons in vitro and in vivo. Electrophysiological studies confirmed that the AMPA/NMDA ratio was reduced in CA1 regions of hippocampal slices from lithium-treated animals. Reduction in GluR1 phosphorylation at its cAMP-dependent protein kinase A site by the synthetic peptide TAT-S845, which mimics the effects of lithium or VPA, was sufficient to attenuate surface and synaptic GluR1/2 levels in hippocampal neurons in vitro and in vivo. Intrahippocampal infusion studies with the AMPA-specific inhibitor GYKI 52466 [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride], a GluR1-specific TAT-S845 peptide, showed that GluR1/2 was essential for the development of manic/hedonic-like behaviors such as amphetamine-induced hyperactivity. These studies provide novel insights into the role of hippocampal GluR1/2 receptors in mediating facets of the manic syndrome and offer avenues for the development of novel therapeutics for these disorders.
双相情感障碍复杂临床症状背后的细胞基础及其有效治疗作用的机制尚未完全阐明。本研究调查了海马突触AMPA受体的作用。我们发现，长期给予抗躁狂药物锂盐和丙戊酸盐（VPA）可在体外和体内降低海马神经元中突触AMPA受体GluR1/2的水平。电生理研究证实，锂盐治疗动物海马切片CA1区的AMPA/NMDA比值降低。合成肽TAT-S845模拟锂盐或VPA的作用，降低了其cAMP依赖性蛋白激酶A位点的GluR1磷酸化，足以在体外和体内减弱海马神经元表面和突触的GluR1/2水平。使用AMPA特异性抑制剂GYKI 52466 [4-(8-甲基-9H-1,3-二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂卓-5-基)-苯甲胺盐酸盐]和GluR1特异性TAT-S845肽进行海马内注射研究表明，GluR1/2对于诸如苯丙胺诱导的多动等躁狂/享乐样行为的发展至关重要。这些研究为海马GluR1/2受体在介导躁狂综合征方面的作用提供了新的见解，并为开发针对这些疾病的新型治疗方法提供了途径。
