Regulation of synaptic transmission by retinoic acid signaling

描述(申请人提供)：突触可塑性被认为塑造神经回路的连通性，并维持神经回路的稳定性，以实现最佳的信息处理。连接性至少在一定程度上是由Hebbian型可塑性决定的，Hebbian型可塑性以一种特定于输入的方式调整电路中突触子集的强度。相反，网络的稳定性是通过稳态突触可塑性来维持的，突触可塑性以乘性方式同时修改神经元的所有突触(称为突触缩放)。我们最近证实，全反式维甲酸(RA)直接作用于突触，通过诱导GluR1型AMPA受体的突触插入来增加突触强度，并且RA的作用对于至少某些形式的内稳态可塑性是必不可少的。此外，我们发现RA可能通过与突触中树突定位的RAR1受体结合发挥作用，RA信号可能与Hebbian型突触的可塑性相交。这些发现使我们得出一个总体假设，即RA是突触中一种新的可扩散信使，通过改变突触后GluR1受体水平来调节突触强度，以响应外部刺激。为了检验这一总体假设，我们提出了三个具体的目标，专注于这一假设中出现的关键问题，并将主要使用海马神经元的生理测量。目的1研究RA在各种形式的动态平衡可塑性和短期突触可塑性中的作用，以探索其作用的共性。这一目标的结果将定义RA在其下运作的生理框架。目的在体外培养的神经元和脑片上，通过条件性缺失RAR1，检测RA与RAR1结合在调节海马区突触强度中的作用，并通过抢救性实验探讨不同RAR1蛋白结构域对其突触功能的相对贡献。目的3在小鼠体内有条件地删除RAR1(与培养制剂相反)，以研究RA介导的突触伸缩和体内Hebbian可塑性之间的功能相互作用。总之，这些实验将利用创新的方法来探索RA和RAR1在海马区突触传递中意想不到的作用，并为它们的作用机制提供初步的见解。这些实验的意义不仅在于它们对理解突触传递的意义，还在于它们与维甲酸相关的神经疾病的潜在相关性，如抑郁症和记忆力丧失。

DESCRIPTION (provided by applicant): Synaptic plasticity is thought to shape the connectivity of neural circuits, and to maintain the stability of neural circuits for optimal information processing. Connectivity is shaped, at least in part, by Hebbian-type plasticity, which adjusts the strength of a subset of synapses in a circuit in an input-specific fashion. In contrast, network stability is maintained via homeostatic synaptic plasticity, which modifies all synapses of a neuron concurrently in a multiplicative fashion (referred to as synaptic scaling). We recently demonstrated that all-trans retinoic acid (RA) directly acts on synapses to increase synaptic strength by inducing the synaptic insertion of GluR1-type AMPA receptors, and that the action of RA is essential for at least some forms of homeostatic plasticity. Moreover, we showed that RA may act by binding to dendritically localized RAR1 receptors in synapses, and that RA-signaling may intersect with Hebbian-type synaptic plasticity. These findings lead us to the overall hypothesis that RA constitutes a novel diffusible messenger in synapses that serves to regulate synaptic strength in response to external stimuli by altering postsynaptic GluR1 receptor levels. To test this overall hypothesis, we propose three specific aims that focus on key questions emerging from this hypothesis, and will primarily employ physiological measurements in hippocampal neurons. Aim 1 will examine the role of RA in various forms of homeostatic plasticity and short-term synaptic plasticity to explore the generality of its action. Results from this aim will define the physiological framework under which RA operates. Aim 2 will test the role of RA-binding to RAR1 in regulating hippocampal synaptic strength using conditional deletion of RAR1 in vitro in cultured neurons and slices, and employ rescue experiments to explore the relative contribution of various RAR1 protein domains to its synaptic function. Aim 3 will conditionally delete RAR1 in mice in vivo (as opposed to culture preparations) to investigate the functional interplay between RA-mediated synaptic scaling and Hebbian plasticity in vivo. Together, these experiments will thus utilize innovative approaches to explore the unexpected role of RA and RAR1 in hippocampal synaptic transmission, and provide initial insights into their mechanism of action. The significance of these experiments not only rests on their implications for understanding of synaptic transmission, but also on their potential relevance for retinoids-related neurological disorders such as depression and memory loses.