METHAMPHETAMINE MODULATES AXONAL GUIDANCE MOLECULES IN MOUSE HIPPOCAMPUS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：在大脑中，在神经发育过程中，轴突的生长或减弱的生长是由不同的受体和配体引导的，这些受体和配体被称为轴突引导分子(AGMs)。在成人大脑中，AGMS影响认知(神经发生、突触可塑性、树突形态)和病理过程(促进/阻止轴突修复)。毒品甲基苯丙胺(METH)的使用者有很高的成瘾、神经毒性和认知障碍的风险，表现为单胺能轴突的修剪或丢失，并伴有海马体功能和神经发生的损害。在我们关于多巴胺受体活性可以改变AGM基因表达的研究的基础上，我们研究了甲基是否改变了海马区AGM的基因表达，海马区是学习、记忆和神经发生的关键脑区。方法：我们比较了5个对照组和5个冰毒(5.0 mg/kg)处理组小鼠海马区Agm-mR-NA的表达，连续给药6天，然后不给药。结果：实时荧光定量聚合酶链式反应检测到成年小鼠全脑中嗜酸性粒细胞表达旺盛：信号素3E、信号素5a、神经粘连蛋白-1、ephinA2、ephinB3、EphB3、EphA4、EphB4、EphB6。与生理盐水对照组相比，冰毒处理组小鼠海马区两种AGM(信号素5a和EphB3)的mRNA表达水平降低。Semaphorin5a是一种AGM，参与轴突的引导和脑血管的发育，EphB3参与维持成熟的神经元连接、突触连接的重新排列和海马轴突脱升。结论：甲硫氨酸可能通过改变轴突导向分子的表达水平而改变海马神经元的形态和功能。可以想象，AGMS有助于冰毒引起的神经毒性和认知能力下降，从而突出冰毒作用的新机制，并引导药物开发。

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.