Cell-Contact Mediated Mechanisms Assembling Synapses

突触的形成和可塑性对大脑的正常功能至关重要， 学习和适应性可塑性的关键事件。成瘾、癫痫、 和阿尔茨海默氏症，涉及适应不良的可塑性似乎劫持这些相同的 控制这些事件的机制导致疾病状态。添加的区域是 考虑到这一疾病对社会的破坏性影响， 比如成瘾行为和新突触的形成和/或适应不良之间的关系 大脑的可塑性变化因此，了解调节 大脑的正常发育和可塑性可能是任何进步的关键。 这些疾病的治疗。 形成的大多数突触接触是在树突棘上形成的，树突棘也是 突触可塑性的关键部位树突棘包含专门的结构，称为 突触后致密物（PSD）直接与突触前神经递质并列 释放位点，并且其大小随突触强度的变化而缩放。尽管 多年来，我一直在研究这种关系， 以及PSD蛋白和突触前蛋白在结构可塑性后的积累 仍然知之甚少。我们的初步数据表明突触前和突触后 蛋白质以模块化的方式与树突棘大小成比例。康贝特人将以 突触的分子结构，并解决如何分子结构的脊椎 突触对结构可塑性的反应有三个目的：1）确定 脊髓突触处谷氨酸受体的纳米结构。2)确定 同步和异步突触释放位点的纳米级组织。 3)确定PSD-95纳米颗粒数量和可塑性是如何调节的。 总的来说，这些研究将促进我们对影响人类行为的基本机制的理解。 神经系统生长和变化的能力，这些事件可能是神经系统的核心。 适应不良的可塑性疾病，如成瘾和阿尔茨海默氏症。

Formation and plasticity of synapses are essential for normal functioning of the brain and key events for learning and adaptive plasticity. Diseases such as addiction, epilepsy, and Alzheimer's that involve maladaptive plasticity appear to highjack these same mechanisms controlling these events leading to disease states. The area of addition is particular pressing given the devastating impact the disease has on society and the clear like between addictive behaviors and the formation of new synapses and/or maladaptive plastic changes in the brain. Therefore, understanding the mechanisms that regulate normal develop and plasticity in the brain are likely to be critical for any advances in treatment of these diseases. The majority of synaptic contacts that form are made on dendritic spines, which are also a key site of synaptic plasticity. Dendritic spines contain specialized structures called postsynaptic densities (PSDs) that are directly apposed to pre-synaptic neurotransmitter release sites and which scale in size with changes in synaptic strength. Despite having understood this relationship for many years, the molecular dynamics of the translocation and accumulation of PSD proteins and presynaptic proteins following structural plasticity remain poorly understood. Our preliminary data indicate that pre- and postsynaptic proteins for scale in a modular fashion with dendritic spine size. We will determine the synaptic molecular architecture and address how the molecular architecture of the spine synapse responds to structural plasticity in three aims: 1) Determine the nanoarchitecture of glutamate receptors at spine synapses. 2) Determine the nanoscale organization of synchronous and asynchronous synaptic release sites. 3) Determine how PSD-95 nanomodule number and plasticity are regulated. Collectively these studies will advance our understand of basic mechanisms that impact the ability of the nervous system to grow and change, events that are likely central to disease of maladaptive plasticity such as addiction and Alzheimer's.