Huang Freesia L, Huang Kuo-Ping, Wu Junfang, Boucheron Catherine
Section on Metabolic Regulation, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510, USA.
J Neurosci. 2006 Jun 7;26(23):6230-7. doi: 10.1523/JNEUROSCI.1182-06.2006.
Environmental enrichment is known to enhance hippocampal neurogenesis and cognitive functions. Neurogranin (Ng), a specific substrate of protein kinase C (PKC), is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng in mice causes severe deficits in spatial learning and long-term potentiation (LTP) in the hippocampal CA1 region. These Ng-/- mice, as compared with Ng+/+, respond poorly after treatment of their hippocampal slices with agents that activate signaling molecules important for learning and memory, including Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII), PKC, protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB). In the present study, adult mice were housed in either regular home cages (control group) or more spacious cages with an exercise wheel and change of toys twice per week (enriched group) for at least 3 weeks. Enriched Ng+/+ and Ng+/- mice showed enhanced LTP in the hippocampal CA1 after high-frequency stimulation, but Ng-/- mice were affected only minimally. Behaviorally, the enriched Ng+/+ and Ng+/-, but not Ng-/- mice, performed significantly better than their respective control cohorts in Morris water maze and in step-down fear conditioning. Enriched Ng+/- mice also showed improvement in the radial arm maze. Quantitative immunoblot analyses showed that the enriched groups of all three genotypes exhibited elevated hippocampal levels of alphaCaMKII and CREB, but not ERK. Interestingly, enrichment caused a significant increase in hippocampal Ng levels both in Ng+/+ and Ng+/- mice that seemed to contribute to their improved LTP and behavioral performances. These results suggest that Ng gates the neuronal signaling reactions involved in learning and memory. During environmental enrichment, these Ng-regulated reactions are also critical for the enhancement of synaptic plasticity and cognitive functions.
已知环境富集可增强海马体神经发生和认知功能。神经颗粒蛋白（Ng）是蛋白激酶C（PKC）的一种特异性底物，在对认知功能至关重要的脑区中大量表达。敲除小鼠体内的Ng会导致海马CA1区的空间学习和长时程增强（LTP）出现严重缺陷。与野生型小鼠（Ng+/+）相比，这些Ng基因敲除小鼠（Ng-/-）在用激活对学习和记忆重要的信号分子（包括钙/钙调蛋白依赖性蛋白激酶II（αCaMKII）、PKC、蛋白激酶A（PKA）、细胞外信号调节激酶（ERK）和环磷酸腺苷反应元件结合蛋白（CREB））的试剂处理海马切片后，反应较差。在本研究中，成年小鼠被饲养在普通饲养笼（对照组）或更宽敞的带有健身轮且每周更换两次玩具的笼子中（富集组），持续至少3周。富集环境下的野生型（Ng+/+）和杂合型（Ng+/-）小鼠在高频刺激后海马CA1区的LTP增强，但Ng基因敲除小鼠（Ng-/-）受到的影响极小。行为学上，富集环境下野生型（Ng+/+）和杂合型（Ng+/-）小鼠在莫里斯水迷宫和阶梯式恐惧条件反射实验中的表现明显优于各自的对照群体，但Ng基因敲除小鼠（Ng-/-）并非如此。富集环境下的杂合型（Ng+/-）小鼠在放射状臂迷宫实验中也表现出改善。定量免疫印迹分析表明，所有三种基因型富集组的海马中αCaMKII和CREB水平均升高，但ERK水平未升高。有趣的是，富集环境使野生型（Ng+/+）和杂合型（Ng+/-）小鼠海马中的Ng水平显著增加，这似乎有助于它们改善LTP和行为表现。这些结果表明，Ng控制着参与学习和记忆的神经元信号反应。在环境富集过程中，这些由Ng调节的反应对于增强突触可塑性和认知功能也至关重要。
