Mechanisms of dendritic exocytosis

描述（由申请人提供）：神经元之间突触耦合或突触强度的调节机制是学习和记忆等关键大脑功能所必需的。改变神经元之间突触强度的过程，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缺失。突触可塑性最强大的形式之一——长时程增强的关键机制是将ampa型神经递质受体从被称为循环内体（REs）的内部囊泡储存中添加到突触后膜上。最近的研究表明，大部分树突棘（兴奋性突触接触的主要部位）含有REs，这些REs与脊柱质膜融合，在突触或附近沉积稳定的AMPA受体库，以响应可塑性诱导活动。这些数据表明，脊柱REs准备局部传递可塑性因子到激活的突触，但许多基本问题仍然存在。例如，为什么这些细胞器存在于某些脊椎中而不存在于其他脊椎中，它们如何通过可塑性诱导刺激与质膜融合，以及融合如何促进突触功能和可塑性是我们在本项目中提出的重要问题。在Aim1中，我们将讨论突触活动的历史是否影响REs在单个突触的分布和/或其AMPA受体的含量。在目标2中，我们将确定单个突触的可塑性是否与脊柱RE含量直接成比例。在Aim3中，我们将剖析将突触活动与脊柱RE融合结合的第二信使和信号分子。结合起来，这些独立但互补的目标将极大地促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）中是如何以及为什么被破坏提供信息。

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.