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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目标：在脑中，轴突生长或衰减生长在神经发育过程中由不同的受体和配体（称为轴突导向分子（AGM））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（促进/阻断轴突修复）。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。基于我们的研究，多巴胺受体活性可以改变AGM mRNA的表达，我们研究了METH是否改变海马AGM的mRNA表达，海马是学习，记忆，神经发生的关键脑区。方法：我们比较了5只对照小鼠和5只METH（5.0 mg/kg）治疗小鼠海马中AGM mRNA的表达，每天给药6次，然后是无治疗日。 研究结果：实时PCR检测到成年小鼠全脑中AGM的稳健mRNA表达：semaphorin 3e、semaphorin 5a、neuropilin-1、ephrinA 2、ephrinB 3、EphB 3、EphA 4、EphB 4、EphB 6。与盐水对照相比，METH处理的小鼠海马中两种AGM（semaphorin 5a和EphB 3）的mRNA表达水平降低。Semaphorin 5a是一种参与轴突引导和脑血管发育的AGM，EphB 3参与维持成熟神经元连接、突触连接重排和海马轴突去束。结论：METH可能通过改变轴突导向分子的表达水平来改变海马的形态和功能。可以想象，AGM有助于METH诱导的神经毒性和认知能力降低，从而突出了METH作用的新机制和药物开发的线索。