Weber Tillmann, Vogt Miriam A, Gartside Sarah E, Berger Stefan M, Lujan Rafael, Lau Thorsten, Herrmann Elke, Sprengel Rolf, Bartsch Dusan, Gass Peter
1] Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany [2] Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
Research Group Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
Neuropsychopharmacology. 2015 May;40(6):1471-84. doi: 10.1038/npp.2014.332. Epub 2014 Dec 30.
Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1(5-HT-/-) mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while α1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1(5-HT-/-) mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.
谷氨酸能系统和血清素能（5-羟色胺，5-HT）系统都与情绪和焦虑的调节有关。下行皮质谷氨酸能神经元通过α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和N-甲基-D-天冬氨酸（NMDA）受体调节中脑缝际核中的5-HT神经元活动。为了分析含GLUA1的AMPA受体在血清素能神经元中的功能作用，我们使用Cre-ERT2/loxP系统，有条件地在成年小鼠的5-HT神经元中选择性失活编码GLUA1的Gria1基因。这些Gria1（5-HT-/-）小鼠表现出明显的焦虑表型，但在运动、抑郁样行为或学习记忆方面没有改变。焦虑相关行为增加与色氨酸羟化酶2（TPH2）的表达和活性显著降低有关，随后缝际核中5-HT及其代谢物5-羟吲哚乙酸（5-HIAA）以及去甲肾上腺素的组织水平降低。然而，5-HT神经元投射区域的TPH2表达和活性以及单胺水平没有变化。对5-HT神经元的细胞外电生理记录显示，虽然α1-肾上腺素能受体介导的兴奋没有改变，但在Gria1（5-HT-/-）小鼠中，对AMPA的兴奋性反应增强，5-HT1A自身受体介导的对5-HT的抑制反应减弱。我们的数据表明，5-HT神经元中GLUA1蛋白的缺失增强了AMPA受体功能，并导致缝际核中发生多种局部分子和神经化学变化，从而使5-HT神经元活动失调并诱发焦虑样行为。
