Elucidating the Roles of GluR1 and BDNF in Trans-synaptic Coordination

描述(由申请人提供)：要了解神经电路是如何根据经验或在疾病中修改的，需要从根本上理解突触前递质释放的变化如何与突触后的反应变化相协调。我研究了一种神经元对慢性不活动的适应模型，在该模型中，包含1-氨基-3-羟基-5-甲基-4-异恶唑-丙酸(AMPA)受体的突触后表达在不活跃期间增加，而在不活跃缓解后突触前释放率增加。此外，这种突触前释放的增加需要通过突触后含有GluR1的AMPA受体和脑源性神经营养因子(BDNF)的信号传递。这些观察结果表明，突触后到突触前的跨突触协调存在，其中含有GluR1的AMPA受体可能启动突触后事件，而BDNF可能作为逆行信使调节突触前功能。然而，GluR1和BDNF在这种跨突触协调中的作用还不完全清楚，它们之间的关系也不清楚。为了解决这些认识上的差距，我将使用生化、遗传学、电生理学和光学方法来确定1)含有GluR1的AMPA受体是如何选择性地在突触后积累的，2)BDNF是否是一个逆行信使，以及3)含有GluR1的受体是如何调节BDNF信号的。阐明GluR1和BDNF在跨突触协调中的作用将促进我们对可塑性机制的基本理解，并可能为突触功能缺陷的疾病提供深入的见解，如阿尔茨海默病和癫痫。 公共卫生相关性：我在了解神经回路连接变化背后的分子机制方面的研究可以为精神障碍带来新的见解，精神障碍是美国导致残疾的主要原因之一。此外，这些见解可以提供新的治疗目标，开辟新的治疗途径，并为这些疾病的潜在治疗铺平道路。因此，这项研究的长期目标是通过可以改善心理健康的发现来改善公共健康。

DESCRIPTION (provided by applicant): Understanding how a neural circuitry is modified from experience or in disease requires a fundamental understanding of how presynaptic changes in transmitter release coordinate with postsynaptic changes in response. I study a model of neuronal adaptation to chronic inactivity in which the postsynaptic expression of surface GluR1-containing 1-amino-3-hydroxyl-5-methyl-4- isoxazole-propionate (AMPA) receptors is increased during the inactivity while the rate of presynaptic release increases after inactivity relief. In addition, this increase in presynaptic release requires flux through the postsynaptic GluR1-containing AMPA receptors and the signaling of brain-derived neurotrophic factor (BDNF). These observations suggest the existence of a post-to-pre trans-synaptic coordination in which GluR1-containing AMPA receptors may initiate the postsynaptic events and BDNF may as a retrograde messenger to regulate presynaptic function. However, the roles of GluR1 and BDNF in this trans-synaptic coordination are incompletely understood and their relationship is unclear. To address these gaps in understanding, I will use biochemical, genetic, electrophysiological and optical methods to determine 1) how GluR1-containing AMPA receptors selectively accumulate at the postsynapse, 2) whether BDNF is a retrograde messenger, and 3) how GluR1-containing receptors regulate BDNF signaling. Elucidating the roles of GluR1 and BDNF in trans-synaptic coordination will advance our fundamental understanding of plasticity mechanisms and is likely to provide insights into diseases in which synaptic function is defective such as in Alzheimer's disease and in epilepsy. PUBLIC HEALTH RELEVANCE: My research in understanding the molecular mechanisms underlying connective changes in neural circuitry can lead to new insights into mental disorders, one of the leading causes of disability in the United States. Moreover, these insights can provide new therapeutic targets, open new avenues of treatments, and pave the road to potential cures for these disorders. Thus, the long-term goal of this research is to improve public health with discoveries that can improve mental health.