Regulation of synaptic transmission by retinoic acid signaling

描述（由申请人提供）：突触可塑性被认为是塑造神经回路的连接性，并保持神经回路的稳定性，以实现最佳信息处理。连接性至少部分地由赫布型可塑性形成，赫布型可塑性以特定于输入的方式调整电路中突触子集的强度。相比之下，网络稳定性是通过稳态突触可塑性来维持的，稳态突触可塑性以乘法方式同时修改神经元的所有突触（称为突触缩放）。我们最近证明，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稳态可塑性是必不可少的。此外，我们发现，RA可能通过结合到树突本地化的RAR 1受体在突触，RA信号可能与赫布型突触可塑性相交。这些研究结果使我们的整体假设，RA构成了一种新的可扩散的信使在突触，用于调节突触强度响应外部刺激，通过改变突触后GluR1受体水平。为了检验这一总体假设，我们提出了三个具体的目标，重点是从这一假设出现的关键问题，并将主要采用海马神经元的生理测量。目的1将研究RA在各种形式的稳态可塑性和短期突触可塑性中的作用，以探索其作用的普遍性。这一目标的结果将定义RA运作的生理框架。目的2将在体外培养的神经元和脑片中使用RAR 1的条件性缺失来测试RA与RAR 1结合在调节海马突触强度中的作用，并采用拯救实验来探索RAR 1蛋白的不同结构域对其突触功能的相对贡献。目的3将有条件地删除小鼠体内的RAR 1（而不是培养制剂），以研究体内RA介导的突触缩放和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在海马突触传递中的意想不到的作用，并对其作用机制提供初步见解。这些实验的意义不仅在于它们对理解突触传递的意义，而且还在于它们与维甲酸相关的神经系统疾病（如抑郁症和记忆丧失）的潜在相关性。

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.