Plasticity in Unitary Synaptic Connections

单一突触连接的可塑性

• 批准号: 8204758
• 负责人: Vernon Daniel MADISON
• 金额: $ 38.38万
• 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/8204758
• 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）：突触后膜表面上特定数量的特定神经递质受体的存在是由许多因素之间复杂的相互作用造成的。就海马兴奋性突触而言，AMPA 受体的特定数量似乎是控制突触强度的主要因素，而它们的特定类型似乎控制着受体数量改变的机制。在这项资助的前（和最初）5年中，我们确定海马突触可塑性，即长时程增强（LTP）、抑制（LTD）及其变化（例如去电位），以状态依赖的方式表现承受可塑性的能力。理解这种国家依赖性至少在两个方面很重要。首先，它可以更好地理解受这种可塑性影响的大脑的大量过程。其次，理解状态依赖的规则可以了解突触可塑性的机制。在这个提案中，我们寻求使用对状态依赖可塑性的理解所提供的规则图来探索这些潜在机制的本质。为此，我们将继续使用从成对的突触连接的海马神经元进行记录的技术，作为从尽可能小的突触群体进行记录的方法，并提供控制突触前或突触后环境的实验能力。已知的突触状态。 LTP 和 LTD 等突触塑性过程在几乎所有试图在细胞水平上解释学习和记忆的模型中都发挥着核心作用。除此之外，LTP 和 LTD 存在于许多大脑区域，并被认为在广泛的神经功能和疾病中发挥作用。人们提出，从恐惧和情绪到记忆再到成瘾的神经功能都在这些可塑过程中奠定了基础。因此，了解这种可塑性背后的机制不仅有助于理解正常的大脑功能，而且有助于理解许多神经和精神疾病。 公共健康相关性：传统上，突触可塑性过程与学习和记忆有关，但事实上，它几乎是大脑所做的一切的基础，并且与各种身体和精神疾病密切相关，包括但当然不限于：阿尔茨海默病、亨廷顿舞蹈病、自闭症、焦虑症、毒瘾、学习障碍等等。发现突触可塑性的潜在机制对于理解多种精神疾病至关重要，在没有这些知识的情况下为这些疾病设计有效的治疗方法和/或治愈方法就像在不了解字母表的情况下试图学习量子物理学一样。这项拟议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疾病的治疗方法提供关键的新知识，从而极大地有助于改善公众的心理健康。