Plasticity at the Excitatory Synapse

描述(申请人提供)：人脑中数十亿个神经元中的每一个都可以有多达10,000个突触。通过建立一个动态的突触连接网络，大脑能够达到人类行为背后的功能复杂性水平。突触的信号传输效率不断地根据经验进行调整。这种突触的可塑性对于大脑发育的微调以及学习和记忆等更高的大脑功能至关重要。突触的可塑性是由对神经元活动和星形胶质细胞功能敏感的过程调节和维持的。现在很清楚，许多神经和精神疾病是由突触传递和可塑性缺陷引起的。因此，了解大脑中调节突触传递的机制对于开发这些疾病的治疗方法至关重要。Conte中心将采用几种方法来研究兴奋性突触可塑性调节所涉及的分子和细胞机制。理查德·胡加尼尔将使用双光子显微镜实时检测体内突触可塑性过程中受体运输的动态。索尔·斯奈德将分析一氧化氮和硫化氢等气体递质如何改变AMPA受体功能和突触可塑性。David Ginty和Alex Kolodkin将研究Sema3F-Npn-2/PlexinA3信号通路如何调节突触结构和功能以及AMPA受体的运输。Paul Worley将分析Oral和STIM1蛋白如何控制细胞内的钙储存，并调节神经元和星形胶质细胞的突触可塑性。德怀特·伯格尔斯将研究星形胶质细胞中的钙信号，以及星形细胞信号如何调节突触的可塑性。大卫·林登将利用活体成像技术研究小脑苔藓纤维神经末梢中钙瞬变的调节，以及行为体验对突触前功能的影响。所有这些项目都以突触为中心，研究突触前、突触后和星形细胞机制如何汇聚在突触上，塑造其形态和功能。了解这些突触传递和可塑性的基本机制将有助于深入了解正常和异常的大脑功能。

DESCRIPTION (provided by applicant): Each of the billions of neurons in the human brain can have up to 10,000 synapses. By establishing a dynamic network of synaptic connections, the brain is able to attain the level of functional complexity that underlies human behavior. The efficiency of signal transmission at synapses is constantly being adapted in response to experience. This synaptic plasticity is critical for the fine-tuning of brain development as well a higher brain function such as learning and memory. The plasticity of synapses is modulated and maintained by processes that are sensitive to neuronal activity and astrocyte function. It is now clear that many neurological and psychiatric diseases result from defects in synaptic transmission and plasticity. Thus, understanding the mechanisms regulating synaptic transmission in the brain is critical for the development of therapeutic treatments for these diseases. The Conte Center will take several approaches to investigate the molecular and cellular mechanisms involved in the regulation of plasticity at the excitatory synapses. Richard Huganir will be examining the dynamics of receptor trafficking during synaptic plasticity in vivo i real time using two-photon microscopy. Sol Snyder will be analyzing how gaseous transmitters like NO and H2S modify AMPA receptor function and synaptic plasticity. David Ginty and Alex Kolodkin will be examining how the Sema3F-Npn-2/PlexinA3 signaling pathway regulates synaptic structure and function and AMPA receptor trafficking. Paul Worley will be analyzing how the Oral and STIM1 proteins control intracellular calcium stores and regulate synaptic plasticity in neurons and astrocytes. Dwight Bergles will be studying calcium signaling in astrocytes and how astrocytic signaling can regulate synaptic plasticity. David Linden will be examining the modulation of calcium transients in mossy fiber nerve terminals in the cerebellum and the effects of behavioral experience on presynaptic function using in vivo imaging techniques. All of these projects center on the synapse and address how presynaptic, postsynaptic and astrocytic mechanisms converge on the synapse to sculpt its morphology and function. Understanding these basic mechanisms of synaptic transmission and plasticity will provide insight into normal and abnormal brain function.