L-kynurenine treatment alters contextual fear conditioning and context discrimination but not cue-specific fear conditioning
L-kynurenine treatment alters contextual fear conditioning and context discrimination but not cue-specific fear conditioning
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DOI：
10.1016/j.bbr.2009.03.013
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发表时间：
2009-08-12
影响因子：
2.7
通讯作者：
Bucci, David J.
中科院分区：
文献类型：
--
作者：
Chess, Amy C.;Landers, Allison M.;Bucci, David J.
神经胶质细胞衍生的分子犬尿酸 (KYNA) 是 α7 烟碱乙酰胆碱受体和 NMDA 受体上甘氨酸 (B) 结合位点的拮抗剂。精神分裂症和阿尔茨海默病患者的大脑和脑脊液中 KYNA 水平升高，这两种疾病的特征都是情境学习和记忆缺陷。本研究测试了这样的假设：KYNA 浓度的增加会损害情境恐惧条件反射，但不会影响特定线索的恐惧条件反射。每个实验中的大鼠均注射载体溶液或 1-犬尿氨酸（L-KYN，100 mg/kg）（KYNA 的前体）。 L-KYN 的给药已被证明可以产生临床相关的 KYNA 浓度增加。在实验 1 中，与对照大鼠相比，L-KYN 治疗的大鼠表现出情境恐惧记忆受损，而对离散听觉提示的恐惧条件反射不受影响。在实验 2 中，训练大鼠区分两种不同的训练环境，一种是提供足部电击，另一种是不与足部电击配对。尽管两组大鼠最终都学会了辨别能力，但 L-KYN 治疗组的大鼠学习速度较慢。实验 3 的结果表明，L-KYN 治疗的大鼠优先使用基本学习策略无法解释上下文辨别的缺陷。总之，这些发现表明，内源性 KYNA 浓度升高会干扰情境学习和记忆，并支持 KYNA 浓度升高可能导致认知功能障碍的观点。此外，这些数据还为新型“神经胶质递质”如何调节神经元功能和行为提供了新的见解。 (C) 2009 Elsevier B.V. 保留所有权利。
The glia-derived molecule kynurenic acid (KYNA) is an antagonist of alpha 7 nicotinic acetylcholine receptors and the glycine(B) binding site on NMDA receptors. KYNA levels are elevated in the brain and cerebrospinal fluid of persons with schizophrenia and Alzheimer's disease, both of which are characterized by deficits in contextual learning and memory. The present study tested the hypothesis that increases in KYNA concentration would impair contextual fear conditioning but spare cue-specific fear conditioning. Rats in each experiment received injections of vehicle solution or 1-kynurenine (L-KYN, 100 mg/kg), the precursor for KYNA. Administration of L-KYN has been shown to produce clinically relevant increases in KYNA concentration. In Experiment 1, L-KYN-treated rats exhibited impaired contextual fear memory compared to control rats, while fear conditioning to a discrete auditory cue was unaffected. In Experiment 2, rats were trained to discriminate between two different training environments, one in which foot shock was delivered and one that was not paired with foot shock. Although both groups of rats eventually learned the discrimination, learning was slower in L-KYN-treated rats. The results of Experiment 3 demonstrated that the deficits in context discrimination could not be explained by the preferential use of an elemental learning strategy by L-KYN-treated rats. Together, these findings indicate that elevated concentration of endogenous KYNA interferes with contextual learning and memory and support the notion that increased concentration of KYNA may contribute to cognitive dysfunction. In addition, these data provide new insight into how novel 'gliotransmitters' may modulate neuronal function and behavior. (C) 2009 Elsevier B.V. All rights reserved.