ALTERED MNEMONIC FUNCTIONS AND RESISTANCE TO N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISM BY FOREBRAIN CONDITIONAL KNOCKOUT OF GLYCINE TRANSPORTER 1
ALTERED MNEMONIC FUNCTIONS AND RESISTANCE TO N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISM BY FOREBRAIN CONDITIONAL KNOCKOUT OF GLYCINE TRANSPORTER 1
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DOI：
10.1016/j.neuroscience.2009.03.056
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发表时间：
2009-06-30
期刊：
影响因子：
3.3
通讯作者：
Boison, D.
中科院分区：
文献类型：
--
作者：
Singer, P.;Yee, K.;Boison, D.
药理学和分子研究的综合证据表明，抑制甘氨酸转运蛋白 1 (GlyT1) 是通过增加谷氨酸能突触附近甘氨酸的细胞外浓度来增强 N-甲基-D-天冬氨酸受体 (NMDAR) 活性的有效手段。然而，这种方法改变认知功能的精确程度和局限性，及其作为针对以认知障碍为标志的精神疾病的治疗策略的潜力，仍有待充分研究。在这里，我们培育了整个前脑（包括神经元和神经胶质细胞）缺乏 GlyT1 的突变小鼠。这种条件性敲除系统可以更精确地检查大脑中 GlyT1 下调对行为和认知的影响。该突变在减弱苯环己哌啶急性 NMDAR 阻断的运动刺激作用方面非常有效，尽管在海马中没有观察到 NMDAR 介导的兴奋性突触后电流 (EPSC) 明显升高。在空间工作记忆和物体识别记忆中观察到认知能力增强，而空间参考记忆和联想学习保持不变。这些发现进一步证实了大脑 GlyT1 抑制的潜在认知增强作用。同时，他们指出了与其他组成型和条件型 GlyT1 敲除系相比潜在的表型差异，并强调了 GlyT1 的神经元和胶质细胞亚群在学习和记忆过程的调节方面可能存在功能差异。这种区别与未来 GlyT1 阻滞剂作为治疗认知障碍的治疗工具的设计的相关性仍有待进一步研究。 (C) 2009 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
Converging evidence from pharmacological and molecular studies has led to the suggestion that inhibition of glycine transporter 1 (GlyT1) constitutes an effective means to boost N-methyl-D-aspartate receptor (NMDAR) activity by increasing the extra-cellular concentration of glycine in the vicinity of glutamatergic synapses. However, the precise extent and limitation of this approach to alter cognitive function, and therefore its potential as a treatment strategy against psychiatric conditions marked by cognitive impairments, remain to be fully examined. Here, we generated mutant mice lacking GlyT1 in the entire forebrain including neurons and glia. This conditional knockout system allows a more precise examination of GlyT1 downregulation in the brain on behavior and cognition. The mutation was highly effective in attenuating the motor-stimulating effect of acute NMDAR blockade by phencyclidine, although no appreciable elevation in NMDAR-mediated excitatory postsynaptic currents (EPSC) was observed in the hippocampus. Enhanced cognitive performance was observed in spatial working memory and object recognition memory while spatial reference memory and associative learning remained unaltered. These findings provide further credence for the potential cognitive enhancing effects of brain GlyT1 inhibition. At the same time, they indicated potential phenotypic differences when compared with other constitutive and conditional GlyT1 knockout lines, and highlighted the possibility of a functional divergence between the neuronal and glia subpopulations of GlyT1 in the regulation of learning and memory processes. The relevance of this distinction to the design of future GlyT1 blockers as therapeutic tools in the treatment of cognitive disorders remains to be further investigated. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.