Synaptic Adaptation and Plasticity After Chronic Disuse

长期废用后的突触适应和可塑性

• 批准号: 7456303
• 负责人: RICHARD W TSIEN
• 金额: $ 34.24万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-16 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7456303
• 关键词: Address; Antiepileptic Agents; Axon; Biochemical; Brain; Calcium; Cells; Chromosome Pairing; Chronic; Class; Clinical; Condition; Dendrites; Disease; Disruption; Dissection; Distal; Down Syndrome; Elements; Ensure; Epilepsy; Event; Face; Feedback; Fire - disasters; Fragile X Syndrome; Frequencies; Genetic Transcription; Glutamate Receptor; Goals; Grant; Green Fluorescent Proteins; Health; Hippocampus (Brain); Inborn Genetic Diseases; Individual; Internet; Intervention; Kinetics; Knowledge; Laboratories; Lead; Learning; Link; Measurement; Memory; Modification; Molecular; Mood Disorders; Motion; Neurons; Output; Pathway interactions; Perforant Pathway; Performance; Pharmaceutical Preparations; Physiology; Production; Property; Proteins; Pyramidal Cells; Range; Rate; Regulation; Relative (related person); Signal Pathway; Signal Transduction; Site; Slice; Source; Spinal; Synapses; Synaptic plasticity; System; Testing; Thinking; Translations; Transport Vesicles; Trees; Up-Regulation; Weight; Work; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; calmodulin-dependent protein kinase II; cognitive function; deprivation; hippocampal pyramidal neuron; millisecond; neuronal cell body; neurotransmission; photoactivation; postsynaptic; presynaptic; relating to nervous system; research study; response; size; trafficking; transmission process

DESCRIPTION (provided by applicant): Synaptic strength must be regulated in the face of changing levels of input in order to ensure that total strength of all inputs are controlled so as to maintain output firing within reasonable limits and these mechanisms must work in conjunction with mechanisms of synaptic plasticity. Its clinical importance can be best illustrated by the condition of epilepsy where these mechanisms are disrupted at the extreme. The association of epilepsy with numerous forms of inherited disorders of cognitive function such as Fragile X and Down Syndrome and the increasing use of anti-epileptic drugs for the treatment of mood disorders highlight the importance of these mechanisms in maintaining normal brain function. This grant proposes to study the underlying mechanisms by which synaptic adaptation is achieved in the face of changing levels of input and the effects of this adaptation on plasticity, building on recent progress in the lab. The first two parts will use strategies to describe more completely the signaling events in the pathway from synaptic input to synaptic modification, taking advantage of the ease of manipulation and measurement in the primary culture system. This part of the study will begin with a careful dissection of the sources of electrical input and calcium entry responsible for the induction of the key signaling events, followed by an elucidation of the mechanisms of regulation of key intermediate signaling products, examining the regulation of their enzymatic activity, stability, transcription, translation and transport to the synapse. In addition, a more complete description of the signaling cascade will be drawn out from microarray studies comparing results from disruption of the signaling pathway at various points. The next part of the study will look closely at the microphysiology of this phenomenon (a) to elucidate the elements of adaptation that are cell-autonomous, by comparing effects of network changes and manipulations in only one cell (b) to describe adaptive changes at the level of single synapses, and (c) to determine the pre- or postsynaptic locus of induction of the various elements of adaptation. These studies will take advantage of long standing expertise in the lab in studying the physiology of single synapses involving focal stimulation and measurement of synaptic responses at unitary sites. The last part of the project will apply the knowledge gained in the previous sections to try to understand the impact of adaptation m intact hippocampal circuits, using the organotypic slice culture. Primary questions addressed will be differences in the expression of adaptation at two different sets of afferents and consequences of this adaptation on the induction and expression of LTP. We will look for forms of LTP not previously found in pyramidal neurons and for changes in the performance of preexisting mechanisms of LTP.

描述(申请人提供)：面对不断变化的输入水平，必须调节突触强度，以确保所有输入的总强度被控制，以便将输出激发保持在合理的范围内，并且这些机制必须与突触可塑性机制一起工作。它的临床重要性可以通过癫痫的情况得到最好的说明，在癫痫的情况下，这些机制被极端地破坏。癫痫与多种形式的遗传性认知功能障碍，如脆性X综合征和唐氏综合症的联系，以及越来越多的抗癫痫药物用于治疗情绪障碍，突显了这些机制在维持正常大脑功能方面的重要性。这项拨款建议在实验室最新进展的基础上，研究面对不断变化的输入水平时实现突触适应的潜在机制，以及这种适应对可塑性的影响。前两部分将使用策略来更完整地描述从突触输入到突触修改的通路中的信号事件，利用在原代培养系统中易于操作和测量的优势。这一部分的研究将首先仔细剖析负责诱导关键信号事件的电输入和钙内流的来源，然后阐明关键中间信号产物的调节机制，研究它们的酶活性、稳定性、转录、翻译和运输到突触的调节。此外，从比较信号通路在不同时间点中断的结果的微阵列研究中将得出信号级联的更完整的描述。该研究的下一部分将密切关注这一现象的微生理学(A)通过比较网络变化和仅在一个细胞中的操纵的影响来阐明细胞自主的适应因素(B)在单个突触水平上描述适应性变化，以及(C)确定各种适应因素在突触前或突触后的诱导位置。这些研究将利用实验室中长期存在的专业知识，研究涉及局部刺激的单个突触的生理学，并测量单一部位的突触反应。该项目的最后部分将应用在前几节中获得的知识，试图通过器官型切片培养来理解适应完整的海马体电路的影响。主要的问题将是适应在两组不同的传入上的表达的差异以及这种适应对LTP的诱导和表达的影响。我们将寻找以前在锥体神经元中没有发现的LTP的形式，以及LTP先前存在的机制的性能变化。