Signaling to and from the Synapse

进出突触的信号

• 批准号: 7692210
• 负责人: Richard L Huganir
• 金额: $ 188.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7692210
• 关键词: AMPA Receptors; Address; Affect; Astrocytes; Attenuated; Axon; Back; Bacterial Artificial Chromosomes; Behavior; Binding; Biochemical; Biological Models; Brain; Breeding; CDK9 Protein Kinase; Calcium; Calcium Signaling; Caring; Cell Death; Cell Nucleus; Cell division; Cells; Collaborations; Complementary DNA; Complex; Core Facility; Coupling; DAP kinase; Daughter; Defect; Dendrites; Development; Disease; Dopamine Receptor; Drug Addiction; Event; Excitatory Synapse; Exhibits; Gene Expression; Genes; Genetic Transcription; Genomic Library; Genomics; Genotype; Glutamate Transporter; Glutamates; Growth; Growth Factor; Human; Immediate-Early Genes; Inositol; Knock-out; Laboratories; Learning; Link; Mediating; Membrane; Memory; Mental disorders; Metabotropic Glutamate Receptors; Molecular; Monitor; Morphology; Movement Disorders; Mus; Mutant Strains Mice; Neuraxis; Neuroglia; Neurologic; Neuronal Plasticity; Neurons; Nucleic Acid Regulatory Sequences; Pathway interactions; Pattern; Phase; Phenotype; Phosphotransferases; Play; Positioning Attribute; Process; Proline; Protein Binding; Protein Biosynthesis; Proteins; Purkinje Cells; Receptor Signaling; Recruitment Activity; Regulation; Relative (related person); Role; Second Messenger Systems; Serum Response Factor; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Small Interfering RNA; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Tilia; Transcription factor genes; base; computerized data processing; cost; depression; experience; extracellular; gain of function; inflammatory pain; insight; interdisciplinary approach; knock-down; loss of function; neuroregulation; neurotransmitter release; novel; postsynaptic; presynaptic; promoter; receptor; reconstitution; relating to nervous system; research study; response; second messenger; small hairpin RNA; success; synaptic function; synaptogenesis; therapy development; transcription factor; transmission process; tripolyphosphate

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.

描述（由申请人提供）：人脑中1000亿个神经元平均有10,000个突触。通过建立突触连接的动态网络，大脑能够达到人类行为的功能复杂性水平。突触时信号传播的效率一直在响应于由神经活动编码的经验而进行调整。这种突触可塑性对于对大脑发育以及更高的大脑功能（例如学习和记忆）的细化至关重要。突触的可塑性是通过对神经元活性和细胞 - 细胞接触敏感的过程进行调节和维护的。反式突触蛋白相互作用引起突触的分化并调节突触的形态和功能。神经递质的释放调节神经元的活性，并激活包括钙信号系统在内的各种第二允许途径，这些途径在调节快速突触可塑性和长期长期变化中通过基因转录激活在突触连接中具有核心作用。这些活性调节的基因然后调节神经元的功能，并可以直接影响突触功能。拟议的孔戴中心将调查诱导突触形成和分化并调节突触功效的突触的细胞内和细胞内信号传导。这些信号转导途径是通过细胞外信号在神经元细胞接触部位启动的，然后将中继到核，最后循环回突触以调节突触功能。拟议的中心汇集了六个领先的实验室在研究突触功能研究中，以采用多种跨学科的协作方法，以研究与调节突触传播和可塑性有关的分子机制。 Richard Huganir将确定与大脑兴奋性突触的形成，分化和调节有关的分子。保罗·沃利（Paul Worley）和索尔·斯奈德（Sol Snyder）将分析兴奋性突触下的大分子信号传导复合物如何控制神经钙信号传导和突触功能。 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将研究谷氨酸转运蛋白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。所有这些项目都集中在突触上，并解决了细胞外和细胞内信号如何在突触上汇聚以雕刻其形态和功能。许多神经系统和精神病疾病是由于突触的发展和/或功能的缺陷而引起的。因此，了解调节大脑突触传播形成和调节的机制对于这些疾病的治疗过程至关重要。