Morice Elise, Billard Jean-Marie, Denis Cécile, Mathieu Flavie, Betancur Catalina, Epelbaum Jacques, Giros Bruno, Nosten-Bertrand Marika
INSERM U513, Neurobiologie et Psychiatrie, 94010 Créteil Cedex, France.
Neuropsychopharmacology. 2007 Oct;32(10):2108-16. doi: 10.1038/sj.npp.1301354. Epub 2007 Mar 7.
Dopamine-mediated neurotransmission has been implicated in the modulation of synaptic plasticity and in the mechanisms underlying learning and memory. In the present study, we tested different forms of activity-dependent neuronal and behavioral plasticity in knockout mice for the dopamine transporter (DAT-KO), which constitute a unique genetic model of constitutive hyperdopaminergia. We report that DAT-KO mice exhibit slightly increased long-term potentiation and severely decreased long-term depression at hippocampal CA3-CA1 excitatory synapses. Mutant mice also show impaired adaptation to environmental changes in the Morris watermaze. Both the electrophysiological and behavioral phenotypes are reversed by the dopamine antagonist haloperidol, suggesting that hyperdopaminergia is involved in these deficits. These findings support the modulation by dopamine of synaptic plasticity and cognitive flexibility. The behavioral deficits seen in DAT-KO mice are reminiscent of the deficits in executive functions observed in dopamine-related neuropsychiatric disorders, suggesting that the study of DAT-KO mice can contribute to the understanding of the molecular basis of these disorders.
多巴胺介导的神经传递与突触可塑性的调节以及学习和记忆的潜在机制有关。在本研究中，我们在多巴胺转运体基因敲除小鼠（DAT-KO）中测试了不同形式的活动依赖性神经元和行为可塑性，该小鼠构成了一种独特的组成性多巴胺能亢进的遗传模型。我们报告称，DAT-KO小鼠在海马CA3-CA1兴奋性突触处表现出长期增强作用略有增加，而长期抑制作用则严重降低。突变小鼠在莫里斯水迷宫中对环境变化的适应能力也受损。电生理和行为表型均被多巴胺拮抗剂氟哌啶醇逆转，表明多巴胺能亢进与这些缺陷有关。这些发现支持多巴胺对突触可塑性和认知灵活性的调节作用。DAT-KO小鼠中出现的行为缺陷让人联想到在多巴胺相关神经精神疾病中观察到的执行功能缺陷，这表明对DAT-KO小鼠的研究有助于理解这些疾病的分子基础。
