Discovering the Fundamental Synaptic Principles of Brain Organization and Function

精确的突触连接的发展是大脑组织的先决条件。虽然突触组织蛋白普遍介导突触发育，但对控制突触发育和功能特异性的分子因素知之甚少。我的NSERC研究计划的长期目标是发现控制大脑组织和功能的基本分子和神经回路机制。在我的NSERC DG的帮助下，我们在揭示海马体、视网膜和中间背丘脑中突触组织和可塑性的基本规则方面取得了重大进展。在接下来的五年中，我们将扩展我们的研究，以研究突触组织蛋白如富含亮氨酸的重复跨膜神经元蛋白（LRRTMs）如何控制大脑分层和可塑性（目标1），调节大型网络的突触活动（目标2），以及通过抑制因子控制突触数量（目标3）。具体目标1：我们将研究LRRTM1和LRRTM2对调节层选择性突触发育和可塑性的贡献。我们的初步工作表明，LRRTM1和LRRTM2富集在特定的树突状层的海马，和Lrrtm1在CA1的缺失损害可塑性在层特异性的方式。我们将比较精确的贡献LRRTM1和LRRTM2在海马CA1树突状层的兴奋性突触的发展和可塑性，在发育中的小鼠大脑和成年小鼠大脑急性损失后。具体目标2。锥体神经元的兴奋性突触活动由快速尖峰小清蛋白（PV+ve）中间神经元网络的前馈抑制调节。中间神经元的抑制作用取决于它们的激活状态，而激活状态是由兴奋性突触传递控制的。我们将研究皮层PV+ve中间神经元上的兴奋性突触组织的机制，该机制使皮层网络的前馈抑制成为可能。具体目标3。我实验室最近的工作表明，glycophosphatidylinositol锚定glypican 4负调控突触发育LRRTM竞争neurexins，真正的突触前LRRTM的合作伙伴。我们发现，磷脂酰肌醇蛋白聚糖4是高度表达的轴突苔藓纤维从齿状回突触到多刺的赘生物，突触后专门的CA 3。我们将评估潜在的抗突触活性磷脂酰肌醇蛋白聚糖4在这个电路使用电路特异性基因修饰，以及一系列的形态和功能测定。重要性：我的研究计划将展示突触如何在特定的大脑区域发展和发挥作用，这是理解大脑中精确神经网络发展的分子机制的关键一步。HQP在尖端神经科学技术方面的跨学科培训将确保他们在工业界和学术界都受到追捧。

The development of accurate synaptic connections is a prerequisite for brain organization. Though synapse organizing proteins mediate synapse development ubiquitously, relatively little is known about the molecular factors governing the specificity of synapse development and function. The long-term objective of my NSERC research program is to discover the fundamental molecular and neural circuit mechanisms governing brain organization and function. Enabled by my NSERC DG, we made significant progress in uncovering essential rules of synapse organization and plasticity in the hippocampus, retina and mediodorsal thalamus. In the next five years, we will extend our studies to investigate how synapse organizing proteins such as leucine rich repeat transmembrane neuronal proteins (LRRTMs) govern brain lamination and plasticity (Obj. 1,) moderate synaptic activity of large networks (Obj. 2), and control synapse numbers via inhibitory factors (Obj. 3). Specific Objective 1: We will investigate the contributions of LRRTM1 and LRRTM2 to regulate lamina-selective synapse development and plasticity. Our preliminary work indicates that LRRTM1 and LRRTM2 are enriched in specific dendritic laminae of the hippocampus, and that deletion of Lrrtm1 in the CA1 impairs plasticity in a layer-specific manner. We will compare the precise contributions of LRRTM1 and LRRTM2 to the development and plasticity of excitatory synapses in the hippocampal CA1 dendritic laminae, in both the developing mouse brain and after acute loss in the adult mouse brain. Specific Objective 2. Excitatory synaptic activity of pyramidal neurons is moderated by feed-forward inhibition by a network of fast-spiking parvalbumin (PV+ve) interneurons. The inhibitory effect of interneurons is dependent on their activation state, which is controlled by excitatory synaptic transmission onto them. We will investigate the mechanisms of excitatory synapse organization on cortical PV+ve interneurons that enables feed-forward inhibition of cortical networks. Specific Objective 3. Recent work in my laboratory indicates that glycophosphatidylinositol anchored glypican4 negatively regulates synapse development by LRRTMs by outcompeting neurexins, the bonafide presynaptic partners of LRRTMs. We found that glypican4 is highly expressed in the axonal mossy fibers from the dentate gyrus that synapse onto thorny excrescences, postsynaptic specializations of CA3. We will assess the potential anti-synaptogenic activities of glypican4 in this circuit using circuit-specific gene modifications, and a range of morphological and functional assays. Significance: My research program will demonstrate how synapses develop and function in specific brain regions, a key step in understanding the molecular mechanisms of the development of precise neural networks in the brain. The transdisciplinary training of HQP in cutting-edge neuroscience techniques will ensure that they are sought after in both industry and academia.