Hippocampal gene expression profiling reveals the possible involvement of Homer1 and GABAB receptors in scopolamine-induced amnesia
Hippocampal gene expression profiling reveals the possible involvement of Homer1 and GABAB receptors in scopolamine-induced amnesia
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DOI：
10.1111/j.1471-4159.2007.04666.x
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发表时间：
2007-09-01
影响因子：
4.7
通讯作者：
Quirion, Remi
中科院分区：
文献类型：
--
作者：
Brouillette, Jonathan;Young, Deborah;Quirion, Remi
东莨菪碱治疗的大鼠通常被用作记忆功能障碍的精神药理学模型，并被广泛研究以确定乙酰胆碱酯酶抑制剂治疗阿尔茨海默病的有效性。东莨菪碱是一种毒蕈碱乙酰胆碱受体拮抗剂，在年轻受试者中引起记忆缺陷，类似于在衰老过程中发生的记忆缺陷。东莨菪碱的健忘症作用已得到证实，但维持其神经药理作用的分子和细胞机制尚不清楚。本研究研究了东莨菪碱处理的成年大鼠在空间记忆任务刺激后的海马基因表达谱。利用微阵列和实时定量RT-PCR方法，我们确定了几个先前已知与记忆过程相关的基因（Homer1， GABA(B)受体，早期生长反应1，prodynorphin， VGF神经生长因子诱导）和多个可能参与认知的新候选基因（包括钙/钙调素依赖性蛋白激酶激酶2，双特异性磷酸酶5和6，糖蛋白C），这些基因在东菪碱治疗后发生了改变。此外，我们发现重组腺相关病毒载体诱导的成年大鼠海马中谷氨酸能成分Homer1a和1c的稳定过表达会破坏东莨菪碱处理大鼠中GABA(B)受体拮抗剂SGS742产生的记忆改善。综上所述，这些结果揭示了东莨菪碱诱导健忘症的新基因和机制，并证明了GABA和谷氨酸神经传递在这种认知功能障碍动物模型中的作用。
Scopolamine-treated rats are commonly used as a psychopharmacological model of memory dysfunction and have been extensively studied to establish the effectiveness of acetylcholinesterase inhibitors in the treatment of Alzheimer's disease. Scopolamine is a muscarinic acetylcholine receptor antagonist that induces memory deficits in young subjects similar to those occurring during aging. The amnesic effect of scopolamine is well established but the molecular and cellular mechanisms that sustain its neuropharmacological action are still unclear. The present genome wide study investigates hippocampal gene expression profiling in scopolamine-treated adult rats following stimulation in a spatial memory task. Using microarray and quantitative real-time RT-PCR approaches, we identified several genes previously known to be associated with memory processes (Homer1, GABA(B) receptor, early growth response 1, prodynorphin, VGF nerve growth factor inducible) and multiple novel candidate genes possibly involved in cognition (including calcium/calmodulin-dependent protein kinase kinase 2, dual specificity phosphatase 5 and 6, glycophorin C) that were altered following scopolamine treatment. Moreover, we found that stable over-expression of glutamatergic components Homer1a and 1c in the hippocampus of adult rats induced by recombinant adeno-associated virus vector abolished memory improvement produced by the GABA(B) receptor antagonist SGS742 in scopolamine-treated rats. Taken together, these results reveal novel genes and mechanisms involved in scopolamine-induced amnesia, and demonstrate the involvement of both GABA and glutamate neurotransmission in this animal model of cognitive dysfunctions.