Mechanisms of dendritic exocytosis

树突状胞吐作用的机制

• 批准号: 9038467
• 负责人: Matthew J Kennedy
• 金额: $ 33.68万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038467
• 关键词: AMPA Receptors; Address; Alzheimer' s Disease; Autistic Disorder; Brain; Cell membrane; Cell physiology; Coupled; Coupling; Cyclic AMP-Dependent Protein Kinases; Data; Dendritic Spines; Deposition; Disease; Endocytosis; Endosomes; Exocytosis; Future; Glutamate Receptor; Health; Hippocampus (Brain); Housing; Individual; Learning; Long-Term Potentiation; Membrane Protein Traffic; Memory; Molecular; N-Methyl-D-Aspartate Receptors; Nature; Neuraxis; Neuronal Plasticity; Neurons; Neurotransmitter Receptor; Optics; Organelles; Pathway interactions; Phosphotransferases; Play; Postsynaptic Membrane; Process; Protein Kinase; Reaction; Receptor Activation; Recording of previous events; Recycling; Role; Schizophrenia; Second Messenger Systems; Signal Transduction; Signaling Molecule; Site; Specificity; Stimulus; Synapses; Synaptic plasticity; Testing; Vertebral column; Work; addiction; cognitive function; density; hippocampal pyramidal neuron; neuropsychiatric disorder; postsynaptic; receptor; research study; response; second messenger; submicron; synaptic function; trafficking

DESCRIPTION (provided by applicant): Mechanisms for regulating the efficacy of synaptic coupling, or synaptic strength, between neurons are required for critical brain functions such as learning and memory. The process of altering synaptic strength between neurons, broadly termed synaptic plasticity, is impaired or absent in numerous neuropsychiatric disorders and diseases. A key mechanism for one of the most robust forms of synaptic plasticity, long-term potentiation, is the addition of AMPA-type neurotransmitter receptors from internal vesicular stores known as recycling endosomes (REs), to the postsynaptic membrane. Recent work has demonstrated that a large fraction of dendritic spines, the major sites of excitatory synaptic contact, contain REs and that these REs undergo fusion with the spine plasma membrane to deposit a stable pool of AMPA receptors at or near the synapse in response to plasticity-inducing activity. These data indicate that spine REs are poised for local delivery of plasticity factors to activated synapses, but many fundamental questions remain. For example, why these organelles are found in some spines but not others, how they are mobilized to fuse with the plasma membrane by plasticity-inducing stimuli, and how fusion contributes to synaptic function and plasticity are important issues we propose to address in this project. In Aim1 we will address whether the history of synaptic activity influences the distribution REs at individual synapses and/or their AMPA receptor content. In Aim2 we will determine whether plasticity at individual synapses directly scales with spine RE content. In Aim3 we will dissect the second messengers and signaling molecules that couple synaptic activity to spine RE fusion. Combined, these independent but complementary aims will greatly advance our understanding of fundamental forms of neuronal plasticity and inform future efforts in determining how and why plasticity is disrupted in numerous neuropsychiatric disorders and diseases including Alzheimer's, autism, schizophrenia and addiction.

描述（由申请人提供）：调节神经元之间突触耦合或突触强度的功效的机制是关键脑功能（如学习和记忆）所必需的。改变神经元之间的突触强度的过程，广义上称为突触可塑性，在许多神经精神障碍和疾病中受损或不存在。突触可塑性的最强形式之一，长时程增强的关键机制是将AMPA型神经递质受体从称为再循环内体（RE）的内部囊泡储存添加到突触后膜。最近的工作表明，大部分的树突棘，兴奋性突触接触的主要网站，包含RE和这些RE进行融合与棘质膜存款一个稳定的池AMPA受体在或附近的突触可塑性诱导活动。这些数据表明，脊柱RE准备为激活的突触局部传递可塑性因子，但许多基本问题仍然存在。例如，为什么这些细胞器被发现在一些棘，而不是其他人，他们是如何动员与质膜融合的可塑性诱导刺激，以及融合如何有助于突触功能和可塑性是我们提出要解决的重要问题在这个项目。在Aim 1中，我们将讨论突触活动的历史是否影响单个突触和/或其AMPA受体含量的分布RE。在Aim 2中，我们将确定单个突触的可塑性是否直接与脊柱RE含量成比例。在目标3中，我们将剖析第二信使和信号分子，耦合突触活动的脊柱RE融合。结合起来，这些独立但互补的目标将大大推进我们对神经元可塑性基本形式的理解，并为未来确定可塑性如何以及为什么在许多神经精神障碍和疾病（包括阿尔茨海默氏症，自闭症，精神分裂症和成瘾）中被破坏的努力提供信息。