Molecular mechanisms of structural plasticity of inhibitory GABAergic interneurons

抽象的。 本研究旨在探讨哺乳动物前脑抑制性GABA能中间神经元（INs）结构可塑性的分子基础。皮质和海马IN在感知和记忆储存中起着关键作用;它们的异常与人类广泛的神经系统疾病有关。众所周知，神经元在感觉体验后会发生形态学变化并重组其网络。这种现象对于发育过程中突触连接的组装和整个生命周期中大脑中信息的处理同样重要，但对潜在的分子机制知之甚少。 通过使用无偏筛选和小鼠遗传学，我们已经确定了调节海马中IN网络结构的转录因子（TF）。我们的初步研究支持这一假设，这些TF是必要的适当的GABA能抑制锥体神经元和记忆存储。我们将使用创新的方法来阐明转录在独特的小鼠模型中的抑制回路中的作用。我们的具体目标是：1）测试在遗传定义的IN亚型中TF的消融如何影响它们的形态、布线和生理学; 2）检查TF信号传导对感觉处理和记忆形成的后果;和3）鉴定TF效应基因。两者合计，这些研究将提供新的和重要的见解到目前为止知之甚少的分子机制的可塑性。

Abstract. This proposal aims to investigate the molecular basis of structural plasticity of inhibitory GABAergic interneurons (INs) in the mammalian forebrain. Cortical and hippocampal INs play critical roles in perception and memory storage; their abnormalities have been associated with a broad spectrum of neurological disorders in humans. It is well-established that INs undergo morphological changes and reorganize their networks after sensory experience. This phenomenon appears to be equally important for assembly of synaptic connectivity during development and for processing of information in the brain across lifespan, but the underlying molecular mechanisms are poorly understood. By using unbiased screening and mouse genetics, we have identified transcription factors (TFs) that regulate the architectures of IN networks in the hippocampus. Our preliminary studies support the hypothesis that these TFs are essential for appropriate GABAergic inhibition of pyramidal neurons and memory storage. We will use innovative approaches to elucidate the role of transcription in inhibitory circuits in unique mouse models. Our specific aims are: 1) To test how ablation of TFs in genetically defined IN subtypes impacts their morphologies, wiring and physiology; 2) To examine the consequences of TF signaling on sensory processing and memory formation; and 3) To identify TF effector genes. Taken together, these studies will provide new and significant insights into thus far poorly understood molecular mechanisms of IN plasticity.