Masneuf Sophie, Lowery-Gionta Emily, Colacicco Giovanni, Pleil Kristen E, Li Chia, Crowley Nicole, Flynn Shaun, Holmes Andrew, Kash Thomas
Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA.
Laboratory of Molecular Neurophysiology, Bowles Center for Alcohol Studies, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
Neuropharmacology. 2014 Oct;85:190-7. doi: 10.1016/j.neuropharm.2014.04.015. Epub 2014 May 4.
The neural factors underlying individual differences in susceptibility to chronic stress remain poorly understood. Preclinical studies demonstrate that mouse strains vary greatly in anxiety-related responses to chronic stress in a manner paralleled by differential stress-induced changes in glutamatergic signaling in the basolateral amygdala (BLA). Previous work has also shown that alterations in the amygdala gene expression of the GluN1 NMDA and the GluK1 kainate receptors are associated with stress-induced alterations in anxiety-like behavior in the C57BL/6J mouse strain. Using in vivo behavioral pharmacological and ex vivo physiological approaches, the aim of the current study was to further elucidate changes in glutamate neurotransmission in the BLA caused by stress and to test the functional roles of GluN1 and GluK1 in mediating stress-related changes in behavior. Results showed that stress-induced alterations in anxiety-like behavior (light/dark exploration test) were absent following bilateral infusion of the GluK1 agonist ATPA into the BLA. Intra-BLA infusion of the competitive NMDA antagonist AP5 produced a generalized behavioral disinhibition/locomotor hyperactivity, irrespective of stress. Slice electrophysiological recordings showed that ATPA augmented BLA GABAergic neurotransmission and that stress increased the amplitude of network-dependent spontaneous excitatory postsynaptic currents and amplitude of GABAergic miniature inhibitory postsynaptic currents in BLA. These findings could indicate stress-induced BLA glutamatergic neuronal network hyperexcitability and a compensatory increase in GABAergic neurotransmission, suggesting that GluK1 agonism augmented GABAergic inhibition to prevent behavioral sequelae of stress. Current data could have implications for developing novel therapeutic approaches, including GluK1 agonists, for stress-related anxiety disorders.
个体对慢性应激易感性差异背后的神经因素仍知之甚少。临床前研究表明，小鼠品系对慢性应激的焦虑相关反应差异很大，其方式与基底外侧杏仁核（BLA）中谷氨酸能信号的应激诱导变化差异平行。先前的研究还表明，GluN1 NMDA和GluK1红藻氨酸受体的杏仁核基因表达改变与C57BL/6J小鼠品系中应激诱导的焦虑样行为改变有关。本研究旨在通过体内行为药理学和体外生理学方法，进一步阐明应激引起的BLA中谷氨酸能神经传递的变化，并测试GluN1和GluK1在介导应激相关行为变化中的功能作用。结果显示，向BLA双侧注入GluK1激动剂ATPA后，应激诱导的焦虑样行为改变（明暗箱探索试验）消失。无论是否存在应激，向BLA内注入竞争性NMDA拮抗剂AP5均会产生全身性行为去抑制/运动亢进。脑片电生理记录显示，ATPA增强了BLA的GABA能神经传递，应激增加了BLA中网络依赖性自发兴奋性突触后电流的幅度以及GABA能微小抑制性突触后电流的幅度。这些发现可能表明应激诱导的BLA谷氨酸能神经元网络兴奋性过高以及GABA能神经传递的代偿性增加，这表明GluK1激动作用增强了GABA能抑制，以预防应激的行为后遗症。目前的数据可能对开发针对应激相关焦虑症的新型治疗方法（包括GluK1激动剂）具有启示意义。
