Interleukin-15 receptor is essential to facilitate GABA transmission and hippocampal-dependent memory.
Interleukin-15 receptor is essential to facilitate GABA transmission and hippocampal-dependent memory.
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DOI：
10.1523/jneurosci.6160-09.2010
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发表时间：
2010-03-31
期刊：
影响因子：
--
通讯作者：
Pan W
中科院分区：
文献类型：
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作者：
He Y;Hsuchou H;Wu X;Kastin AJ;Khan RS;Pistell PJ;Wang WH;Feng J;Li Z;Guo X;Pan W
白细胞介素-15（IL-15）是一种由正常脑组织产生的细胞因子，但IL-15系统在正常成人中的功能尚不清楚。海马IL 15系统对记忆巩固至关重要的假设通过使用IL 15 R α敲除小鼠进行行为、生化、免疫组织学和电子显微镜分析来验证。敲除小鼠表现出记忆缺陷，这是通过斯通T型迷宫和恐惧条件反射来确定的。在它们的大脑中，γ-氨基丁酸（GABA）的浓度显著降低。GABA合成酶谷氨酸脱羧酶（GAD）的区域特异性变化，在海马CA 1区的起始层中GAD-67免疫阳性中间神经元增加，伴随着CA 3区GAD-67突触的非显著减少。Western印迹显示海马匀浆中GAD-65增加，但GAD-67没有增加。在基因敲除小鼠中，海马的超微结构保持完整。为了进一步验证IL 15通过再摄取机制直接调节GABA周转的假设，在两种神经元细胞系中测定了IL 15对3 H-GABA摄取的剂量-反应关系。有效和无毒剂量进一步用于突触体摄取研究。IL 15可降低野生型小鼠前脑突触体对~ 3 H-GABA的摄取。与此一致，IL 15 R α敲除小鼠的突触体摄取3 H-GABA增加。总之，结果显示了一种独特的细胞因子通过调节GABA传递在正常海马活动中的新功能。
Interleukin-15 (IL15) is a cytokine produced by normal brain, but the functions of the IL15 system in normal adults are not yet clear. The hypothesis that the hippocampal IL15 system is essential for memory consolidation was tested by use of IL15Rα knockout mice in behavioral, biochemical, immunohistological, and electron microscopic analyses. The knockout mice showed deficits in memory, determined by the Stone T-maze and fear conditioning. In their hippocampi, the concentration of γ-aminobutyric acid (GABA) was significantly lower. There were region specific changes of the GABA synthesizing enzyme glutamic acid decarboxidase (GAD), with increased GAD-67 immunopositive interneurons in the stratum oriens of the CA1 region of the hippocampus, accompanied by non-significant reduction of GAD-67 synapses in the CA3 region. Western blotting showed an increase of GAD-65, but not GAD-67, in the hippocampal homogenate. The ultrastructure of the hippocampus remained intact in the knockout mice. To further test the hypothesis that IL15 directly modulates GABA turnover by reuptake mechanisms, the dose-response relationship of IL15 on 3H-GABA uptake was determined in two neuronal cell lines. The effective and non-toxic dose was further used in the synaptosomal uptake studies. IL15 decreased the uptake of 3H-GABA in synaptosomes from the forebrain of wildtype mice. Consistent with this, IL15Rα knockout mice had increased synaptosomal uptake of 3H-GABA. Overall, the results show novel functions of a unique cytokine in normal hippocampal activity by regulating GABA transmission.