Signaling to and from the Synapse

描述(申请人提供)：人脑中的1000亿个神经元平均有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神经活动编码的经验进行调整。这种突触的可塑性对大脑发育的微调以及学习和记忆等高级大脑功能至关重要。突触的可塑性是通过对神经元活动和细胞间接触敏感的过程来调节和维持的。跨突触蛋白相互作用诱导突触分化，调节突触的形态和功能。神经递质的释放调节神经元的活动，并激活包括钙信号系统在内的多种第二信使通路，这些通路通过激活基因转录，在调节突触的快速可塑性和突触连接的长期变化中发挥核心作用。这些活性调节基因然后调节神经元的功能，并可以直接影响突触功能。拟建的Conte中心将研究进出突触的细胞间和细胞内信号，这些信号诱导突触的形成和分化，并调节突触的功效。这些信号转导通路由细胞外信号在神经细胞接触处启动，然后传递到细胞核，最后循环回到突触，调节突触功能。拟建的中心汇集了突触功能研究领域的六个领先实验室，采取多种跨学科协作方法，研究参与调节突触传递和可塑性的分子机制。理查德·胡加尼尔将识别与大脑中兴奋性突触的形成、分化和调节有关的分子。Paul Worley和Sol Snyder将分析兴奋性突触上的大分子信号复合体如何控制神经元钙信号和突触功能。大卫·林登和大卫·金蒂将分析钙如何调节神经元转录因子和基因表达。德怀特·伯格尔斯将研究谷氨酸转运体和代谢型谷氨酸受体的相互作用，以及这种相互作用在调节突触功能中的作用。所有这些项目都以突触为中心，研究细胞外和细胞内信号如何汇聚到突触上，以塑造其形态和功能。许多神经和精神疾病是由突触的发育和/或功能缺陷引起的。因此，了解大脑中突触传递的形成和调节机制对于开发这些疾病的治疗方法至关重要。

DESCRIPTION (provided by applicant): The 100 billion neurons in the human brain have an average of 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 as encoded by neural activity. This synaptic plasticity is critical for the fine- tuning of brain development as well as 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 cell-cell contact. Trans-synaptic protein interactions induce differentiation of the synapse and regulate the morphology and function of synapses. Release of neurotransmitter regulates the activity of the neuron and activates a variety of second messenger pathways including calcium-signaling systems, which have a central role in regulating both rapid synaptic plasticity and long-term changes in synaptic connections through the activation of gene transcription. These activity-regulated genes then modulate the function of the neuron and can directly affect synapse function. The proposed Conte Center will investigate the inter- and intracellular signaling to and from the synapse that induce synapse formation and differentiation and regulate synaptic efficacy. These signal transduction pathways are initiated at sites of neuronal cell contact by extracellular signals and are then relayed to the nucleus and finally cycle back to the synapse to regulate synaptic function. The proposed Center brings together six leading laboratories in the study of synaptic function to take multiple interdisciplinary collaborative approaches to investigate the molecular mechanisms involved in regulating synaptic transmission and plasticity. Richard Huganir will be identifying molecules involved in the formation, differentiation and regulation of excitatory synapses in the brain. Paul Worley and Sol Snyder will be analyzing how macromolecular signaling complexes at excitatory synapses control neuronal calcium signaling and synaptic function. David Linden and David Ginty will be analyzing how calcium regulates neuronal transcription factors and gene expression. Dwight Bergles will be studying the interaction of glutamate transporters and metabotropic glutamate receptors and the role of this interaction in regulating synaptic function. All of these projects center on the synapse and address how extracellular and intracellular signals converge on the synapse to sculpt its morphology and function. Many neurological and psychiatric diseases result from defects in the development and/or function of synapses. Thus, understanding the mechanisms regulating the formation and modulation of synaptic transmission in the brain is critical for the development of treatments for these diseases.