Plasticity in Unitary Synaptic Connections

单一突触连接的可塑性

• 批准号: 8011531
• 负责人: Vernon Daniel MADISON
• 金额: $ 38.28万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011531
• 关键词: AMPA Receptors; Alzheimer' s Disease; Anxiety Disorders; Area; Autistic Disorder; Brain; Chemosensitization; Complex; D Aspartate; Dependence; Depressed mood; Disease; Drug Addiction; Emotions; Endocytosis; Environment; Excision; Excitatory Synapse; Frequencies; Fright; Grant; Hippocampus (Brain); Homosynaptic Depression; Huntington Disease; Individual; Knowledge; Learning; Learning Disabilities; Long-Term Depression; Long-Term Potentiation; Maps; Membrane; Memory; Mental Depression; Mental Health; Mental disorders; Methods; Modeling; N-Methyl-D-Aspartate Receptors; Nature; Neurons; Neurophysiology - biologic function; Neurotransmitter Receptor; Physics; Plastics; Play; Population; Postsynaptic Membrane; Process; Property; Public Health; Publishing; Research; Role; Specific qualifier value; Surface; Synapses; Synaptic Membranes; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Variant; addiction; aspartate receptor; base; design; effective therapy; nervous system disorder; postsynaptic; public health relevance; quantum; receptor; therapy design; trafficking

DESCRIPTION (provided by applicant): The presence of particular neurotransmitter receptors in particular numbers on the surface of the postsynaptic membrane results from a complex interplay between many factors. In the case of hippocampal excitatory synapses, the particular number of AMPA receptors appears to be the main factor that controls synaptic strength, while their particular type appears to control the mechanisms by which the number of receptors can be changed. In the prior (and initial) 5 years of this grant, we established that hippocampal synaptic plasticity, namely long-term potentiation (LTP), depression (LTD) and its variations (e.g. depotentiation), behave in a state-dependent manner with respect to the ability to undergo plasticity. Understanding this state-dependence is important in at least two respects. First, it provides greater understanding of the large number of processes of the brain that are influenced by this plasticity. Second, understanding the rules of state-dependence informs as to the mechanisms that underlie synaptic plasticity. In this proposal, we seek to use the rule-map that an understanding of state-dependent plasticity provides to probe for the nature of these underlying mechanisms. To do so, we will continue to use the technique of recording from pairs of synaptically connected hippocampal neurons as a way of recording from the smallest possible populations of synapses, and which provides the experimental ability to control the pre-or postsynaptic environment of synapses in known synaptic states. Synaptic plastic processes such as LTP and LTD play a central role in virtually all models that seek to explain learning and memory at a cellular level. Beyond even that, LTP and LTD are found in many brain areas and have been proposed to play a role in a wide range of neural functions and disorders. Neural functions from fear and emotion, through memory to addiction have been proposed to have a basis in these plastic processes. Therefore, the understanding of the mechanisms that underlie this plasticity will provide wide-ranging benefits not only to understanding normal brain function, but also many neurological and mental disorders. PUBLIC HEALTH RELEVANCE: The processes of synaptic plasticity have traditionally been associated with learning and memory, but in fact underlie practically everything the brain does, and have been strongly implicated in a variety of physical and mental disorders, including, but certainly not limited to: Alzheimer's disease, Huntington's disease, autism, anxiety disorders, drug addiction, learning disabilities, and many more. Discovery of the underlying mechanisms of synaptic plasticity is so fundamental to understanding scores of mental disorders, that designing effective treatments and/or cures for these disorders without this knowledge would be akin to trying to learn quantum physics without first knowing the alphabet. The relevance of this proposed research to public health is that it will provide new knowledge key to designing treatments for many nervous and mental disorders, and thus, will greatly assist in the improvement of the public's mental health.

描述(由申请人提供)：突触后膜表面存在特定数量的特定神经递质受体是许多因素之间复杂相互作用的结果。在海马区兴奋性突触的情况下，特定数量的AMPA受体似乎是控制突触强度的主要因素，而它们特定的类型似乎控制着受体数量变化的机制。在这项资助的前5年(和最初的5年)，我们确定了海马区突触的可塑性，即长时程增强(LTP)、抑制(LTD)及其变异(如去增强)，在经历可塑性的能力方面表现为状态依赖的方式。理解这种对国家的依赖至少在两个方面很重要。首先，它提供了对大脑受这种可塑性影响的大量过程的更好的理解。其次，了解状态依赖的规则有助于了解突触可塑性背后的机制。在这个提议中，我们试图使用对状态依赖可塑性的理解提供的规则图来探索这些潜在机制的性质。为此，我们将继续使用从突触连接的海马神经元对进行记录的技术，作为从尽可能小的突触群体进行记录的一种方式，并提供控制已知突触状态下突触的突触前或突触后环境的实验能力。突触的可塑性过程，如LTP和LTD，在几乎所有试图在细胞水平上解释学习和记忆的模型中发挥着核心作用。除此之外，LTP和LTD在大脑的许多区域都被发现，并被认为在广泛的神经功能和疾病中发挥作用。从恐惧和情绪，到记忆再到上瘾的神经功能被认为是这些可塑性过程的基础。因此，了解这种可塑性的机制将不仅对了解正常的大脑功能，而且对许多神经和精神障碍提供广泛的好处。 公共卫生相关性：突触可塑性的过程传统上与学习和记忆有关，但实际上是大脑所做的一切的基础，并与各种身体和精神疾病密切相关，包括但肯定不限于：阿尔茨海默病、亨廷顿病、自闭症、焦虑症、药物成瘾、学习障碍等等。突触可塑性的潜在机制的发现对于理解数十种精神障碍是如此基础，以至于在没有这些知识的情况下设计针对这些疾病的有效治疗和/或治疗将类似于试图在不首先了解字母表的情况下学习量子物理。这项拟议的研究与公共卫生的相关性在于，它将为设计许多神经和精神障碍的治疗方案提供新的知识关键，从而将极大地帮助改善公众的心理健康。