Plasticity in Unitary Synaptic Connections

单一突触连接的可塑性

• 批准号: 7786398
• 负责人: Vernon Daniel MADISON
• 金额: $ 38.58万
• 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/7786398
• 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; Neurologic; 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; postsynaptic; presynaptic; 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引起的。在海马兴奋性突触的情况下，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可以改变的机制。在此授权的前（和最初）5年，我们确定了海马突触可塑性，即长时程增强（LTP），抑郁症（LTD）及其变化（例如去增强），表现在状态依赖的方式方面的能力进行可塑性。理解这种状态依赖至少在两个方面是重要的。首先，它提供了更多的了解大脑的大量过程，这些过程受到这种可塑性的影响。其次，了解状态依赖的规则有助于了解突触可塑性的机制。在这个建议中，我们试图使用规则图，状态依赖可塑性的理解提供了探测这些潜在机制的性质。为了做到这一点，我们将继续使用从突触连接的海马神经元对记录的技术，作为从最小可能的突触群体记录的一种方式，它提供了在已知突触状态下控制突触前或突触后环境的实验能力。突触可塑性过程，如LTP和LTD，在几乎所有试图从细胞水平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还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。人们认为，从恐惧和情感、记忆到成瘾的神经功能都在这些可塑性过程中有基础。因此，理解这种可塑性的机制不仅对理解正常的大脑功能，而且对许多神经和精神疾病都有广泛的益处。 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几乎所有事情的基础，并且与各种身体和精神障碍密切相关，包括但不限于：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。发现突触可塑性的潜在机制对于理解许多精神疾病是非常重要的，如果没有这些知识，设计有效的治疗和/或治愈这些疾病的方法就像是在不知道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，它将提供对设计许多神经和精神障碍治疗方法至关重要的新知识，因此将极大地有助于改善公众的心理健康。