Improved Reversal Learning and Working Memory and Enhanced Reactivity to Novelty in Mice with Enhanced GABAergic Innervation in the Dentate Gyrus
Improved Reversal Learning and Working Memory and Enhanced Reactivity to Novelty in Mice with Enhanced GABAergic Innervation in the Dentate Gyrus
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DOI：
10.1093/cercor/bhq017
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发表时间：
2010-11-01
期刊：
影响因子：
3.7
通讯作者：
Schachner, Melitta
中科院分区：
文献类型：
--
作者：
Morellini, Fabio;Sivukhina, Elena;Schachner, Melitta
兴奋和抑制之间的平衡控制着海马体功能的基本方面。在这里，我们报告了在缺乏细胞外基质糖蛋白tenascin-R(TNR)的麻醉成年小鼠中，齿状回抑制/兴奋神经元的比率增加，伴随着伽马氨基丁酸(GABA(A))受体依赖性突触可塑性的损害和兴奋性的活动依赖性变化。与野生型小鼠相比，TNR缺陷小鼠表现出更快的反向学习、改善的工作记忆和对新奇事物的反应能力。值得注意的是，在野生型和TNR缺陷小鼠中，较快的反向学习速度在个体动物水平上与小白蛋白阳性中间神经元与颗粒细胞的比率以及颗粒细胞体细胞上小白蛋白阳性终末的密度相关。我们的研究结果表明，通过消融TNR来修饰细胞外基质导致了齿状回的新的结构和功能设计，增强了GABA能神经支配，即增加了抑制性细胞与兴奋性细胞的比率，改变了可塑性，促进了工作记忆和逆转学习。在野生型小鼠中，齿状回中抑制细胞与兴奋细胞比率的提高也与逆转学习呈正相关，表明抑制水平独立于TNR基因调节学习的特定方面。
The balance between excitation and inhibition controls fundamental aspects of the hippocampal function. Here, we report an increase in the ratio of inhibitory to excitatory neurons in the dentate gyrus, accompanied by gamma-aminobutyric acid(A) (GABA(A)) receptor-dependent impairment of synaptic plasticity and enhancement of activity-dependent changes in excitability in anesthetized adult mice deficient for the extracellular matrix glycoprotein tenascin-R (TNR). TNR-deficient mice showed faster reversal learning, improved working memory, and enhanced reactivity to novelty than wild-type littermates. Remarkably, in wild-type and TNR-deficient mice, faster reversal learning rates correlated at the individual animal level with ratios of parvalbumin-positive interneurons to granule cells and densities of parvalbumin-positive terminals on somata of granule cells. Our data demonstrate that modification of the extracellular matrix by ablation of TNR leads to a new structural and functional design of the dentate gyrus, with enhanced GABAergic innervation, that is, enhanced ratio of inhibitory to excitatory cells, and altered plasticity, promoting working memory and reversal learning. In wild-type mice, the enhanced ratio of inhibitory to excitatory cells in the dentate gyrus also positively correlated with reversal learning, indicating that level of inhibition regulates specific aspects of learning independent of the TNR gene.