Signaling to and from the Synapse

描述（申请人提供）：人类大脑中有1000亿个神经元，平均有1万个突触。通过建立突触连接的动态网络，大脑能够达到构成人类行为基础的功能复杂性水平。突触的信号传输效率不断被调整，以响应由神经活动编码的经验。这种突触可塑性对于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。突触的可塑性是由对神经元活动和细胞间接触敏感的过程调节和维持的。跨突触蛋白相互作用诱导突触分化，调控突触形态和功能。神经递质的释放调节神经元的活动，激活包括钙信号系统在内的多种第二信使通路，钙信号系统通过基因转录的激活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。这些活动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。提议的Conte中心将研究突触之间和突触之间的细胞间和细胞内信号传导，诱导突触的形成和分化，并调节突触的功效。这些信号转导途径由细胞外信号在神经元细胞接触部位启动，然后传递到细胞核，最后循环回突触，调节突触功能。该中心汇集了六个领先的突触功能研究实验室，采用多学科合作的方法来研究调节突触传递和可塑性的分子机制。Richard Huganir将负责识别参与大脑兴奋性突触形成、分化和调节的分子。Paul Worley和Sol Snyder将分析兴奋性突触中的大分子信号复合物如何控制神经元钙信号和突触功能。David Linden和David Ginty将分析钙如何调节神经元转录因子和基因表达。Dwight Bergles将研究谷氨酸转运体和代谢性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，从而塑造突触的形态和功能。许多神经和精神疾病是由突触发育和/或功能缺陷引起的。因此，了解大脑突触传递的形成和调节机制对这些疾病的治疗至关重要。

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.