METHAMPHETAMINE MODULATES AXONAL GUIDANCE MOLECULES IN MOUSE HIPPOCAMPUS

甲基苯丙胺调节小鼠海马体中的轴突引导分子

• 批准号: 8172878
• 负责人: Bertha K Madras
• 金额: $ 1.81万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172878
• 关键词: Adult; Attenuated; Axon; Brain; Brain region; Cognition; Computer Retrieval of Information on Scientific Projects Database; Development; Dopamine Receptor; Drug user; Funding; Grant; Growth; Hippocampus (Brain); Impaired cognition; Institution; Learning; Ligands; Memory; Methamphetamine; Morphology; Mus; Neurons; Neuropilin-1; Pathologic Processes; Pharmaceutical Preparations; Research; Research Personnel; Resources; Saline; Source; Synapses; Synaptic plasticity; Time; United States National Institutes of Health; addiction; axon growth; axonal guidance; base; high risk; mRNA Expression; neurodevelopment; neurogenesis; neurotoxicity; receptor; repaired; treatment duration

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AIMS: In brain, axon growth or attenuated growth is guided by diverse receptors and ligands, designated axonal guidance molecules (AGMs), during neurodevelopment. In the adult brain, AGMs influence cognition (neurogenesis, synaptic plasticity, dendritic morphology) and pathological processes (promotion/blockade of axonal repair). Users of the drug methamphetamine (METH) are at high risk for addiction, neurotoxicity and cognitive impairment, manifest by pruning or losses in monoaminergic axons combined with impaired hippocampal function and neurogenesis. Based on our research that dopamine receptor activity can alter AGM mRNA expression, we investigated whether METH alters mRNA expression of AGMs in hippocampus, a brain region critical for learning, memory, neurogenesis. METHODS: We compared AGM mRNA expression in hippocampus of 5 control and 5 METH (5.0 mg/kg) treated mice, administered daily for 6, followed by a no treatment day. RESULTS: Real-time PCR detected robust mRNA expression of AGMs in adult whole mouse brain: semaphorin3e, semaphorin5a, neuropilin-1, ephrinA2, ephrinB3, EphB3, EphA4, EphB4, EphB6. mRNA expression levels of two AGMs (semaphorin5a and EphB3) were reduced in hippocampus of METH treated mice compared with saline controls. Semaphorin5a is an AGM implicated in axonal guidance and development of brain vasculature, and EphB3 is implicated in maintaining mature neuronal connections, re-arrangement of synaptic connections, and in hippocampal axon defasciculation. CONCLUSIONS: METH may alter hippocampal morphology and function by changing expression levels of axonal guidance molecules. Conceivably, AGMs contribute to METH-induced neurotoxicity and reduced cognition, thereby highlighting new mechanisms of METH action and leads for medications development.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目的：在大脑中，轴突生长或减弱生长在神经发育过程中受到不同受体和配体（称为轴突引导分子（AGM））的引导。在成人大脑中，AGM 影响认知（神经发生、突触可塑性、树突形态）和病理过程（轴突修复的促进/阻断）。甲基苯丙胺（METH）药物的使用者具有成瘾、神经毒性和认知障碍的高风险，表现为单胺能轴突的修剪或损失以及海马功能和神经发生受损。基于多巴胺受体活性可以改变 AGM mRNA 表达的研究，我们研究了冰毒是否会改变海马体中 AGM 的 mRNA 表达，海马体是一个对学习、记忆和神经发生至关重要的大脑区域。方法：我们比较了 5 只对照小鼠和 5 只接受 METH (5.0 mg/kg) 治疗的小鼠海马中 AGM mRNA 的表达，每天给药 6 次，然后不进行治疗。 结果：实时 PCR 检测到成年小鼠全脑中 AGM 的强劲 mRNA 表达：semaphorin3e、semaphorin5a、neuropilin-1、ephrinA2、ephrinB3、EphB3、EphA4、EphB4、EphB6。与盐水对照组相比，METH 治疗小鼠海马中两种 AGM（semaphorin5a 和 EphB3）的 mRNA 表达水平降低。 Semaphorin5a 是一种 AGM，与轴突引导和脑脉管系统的发育有关，而 EphB3 与维持成熟的神经元连接、突触连接的重新排列以及海马轴突解束有关。结论：冰毒可能通过改变轴突引导分子的表达水平来改变海马的形态和功能。可以想象，AGM 会导致 METH 引起的神经毒性和认知能力下降，从而凸显 METH 作用的新机制并为药物开发提供线索。