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

描述（由申请人提供）：了解神经回路如何因经验或疾病而改变，需要对递质释放的突触前变化如何与突触后反应变化协调有基本的了解。我研究了一个神经元对慢性不活动的适应模型，其中在不活动期间，含有1-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的表面glur1的突触后表达增加，而在不活动缓解后，突触前释放率增加。此外，突触前释放的增加需要通过含有glur1的突触后AMPA受体和脑源性神经营养因子（BDNF）的信号传导。这些观察结果表明存在一种后-前跨突触协调，其中含有glur1的AMPA受体可能启动突触后事件，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尚不完全清楚，它们之间的关系也不清楚。为了解决这些理解上的空白，我将使用生化、遗传、电生理和光学方法来确定1)含glur1的AMPA受体如何在突触后选择性积累，2)BDNF是否是逆行信使，以及3)含glur1的受体如何调节BDNF信号传导。阐明GluR1和BDNF在跨突触协调中的作用将推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（如阿尔茨海默病和癫痫）提供见解。

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.