Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
PLoS One. 2012;7(7):e40555. doi: 10.1371/journal.pone.0040555. Epub 2012 Jul 5.
Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear.
We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0)--a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity.
Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD.
尽管大量研究表明，在正常学习和记忆以及阿尔茨海默病（AD）中健忘症的发病机制中，海马齿状回中的兴奋性颗粒神经元很重要，但控制颗粒神经元活动的颗粒下 GABA 能抑制性中间神经元的作用仍不清楚。
我们通过 Cre 依赖性病毒表达增强的盐藻视蛋白（eNpHR3.0）——一种光驱动氯离子泵，来抑制其活性，从而探索了颗粒下 GABA 能抑制性中间神经元在空间学习和记忆中的功能。通过将包含编码 eNpHR3.0 的双 floxed 反向开放阅读框的腺相关病毒双侧注射到表达 Cre 重组酶的齿状回颗粒下，实现了颗粒下 GABA 能中间神经元特异性表达 eNpHR3.0，该 Cre 重组酶受 GABA 能中间神经元特异性增强子的控制。用黄色激光进行体外和体内照射可引发颗粒下 GABA 能中间神经元的抑制，进而导致齿状回颗粒神经元的激活，而不会影响海马 CA3 和 CA1 区的锥体神经元。我们发现，光遗传抑制颗粒下 GABA 能中间神经元活性会损害空间学习和记忆检索，而不会影响莫里斯水迷宫测试中的记忆保留。重要的是，光遗传抑制颗粒下 GABA 能中间神经元活性不会改变短期工作记忆、运动协调或探索性活动。
我们的发现确立了颗粒下 GABA 能中间神经元活性在控制空间学习和记忆检索中的关键作用，并为 GABA 能中间神经元损伤可能导致 AD 中健忘症的发病机制提供了证据。
