Molecular mechanisms of synapse development and specificity

神经细胞之间高度特异性的连接模式是大脑组织和功能的基本原则。这些被称为突触的特殊连接的发展涉及一系列不同的过程，包括轴突瞄准特定区域或层，识别和参与特定细胞类型的树突区域的分子靶标，突触前和突触后的分化以及具有特征分子身份和功能特性的突触的成熟。一类被称为突触组织蛋白的粘附蛋白介导了突触发育的多个步骤。尽管它们在突触形成中的作用已经得到了很好的研究，但它们对突触特异性的贡献却很少被探索。在这个拟议的研究项目中，我的HQP， 1名博士生和2名硕士学生，以及我将研究富含亮氨酸的重复跨膜神经元（LRRTM）突触组织者家族如何促进突触特异性。LRRTMs在离散细胞群和树突层中表达，因此非常适合介导层特异性突触的发育。我们的第一个目标是确定LRRTM1和LRRTM2对海马层选择性突触发育的贡献。我们的第二个目标是剖析LRRTMs介导突触发育的分子机制。最后，通过体内操作，我们建议测试突触组织蛋白通过替代途径功能是否可以恢复从出生开始缺乏lrrtm的小鼠突触回路的缺陷。我们预计LRRTM1和LRRTM2分别在海马CA1辐射层和空洞层分子中对选择性突触的发育起重要作用，并且它们需要同时参与突触前和突触后结合伙伴来介导双向突触的发育。尽管层压是脊椎动物和无脊椎动物大脑的中心组织原理，但最近的大规模筛选项目指出，粘附蛋白在特定细胞群和大脑区域中有选择性地表达。虽然这一提议将直接解决突触特异性在内嗅皮层-CA1和CA3 Schaffer侧枝-CA1突触通路的起源，但其结果有望代表神经回路的形成，因此将引起更广泛的神经科学界的极大兴趣。

Highly specific patterns of connectivity among nerve cells is a fundamental principle of brain organization and function. The development of these specialized connections known as synapses involves a series of distinct processes including targeting of axons to defined zones or laminae, recognition and engagement with molecular targets on select dendritic regions of specific cell-types, pre- and post-synaptic differentiation and maturation of synapses with characteristic molecular identities and functional properties. A class of adhesion proteins known as synapse organizing proteins mediates multiple steps of synapse development. Whereas their roles in synapse formation have been well studied, their contribution to synaptic specificity is less well explored. Under this proposed research program, my HQP, 1 Ph.D. student and 2 M.Sc. students, and I will address how leucine-rich repeat transmembrane neuronal (LRRTM) family of synapse organizers contributes to synaptic specificity. The LRRTMs are expressed in discrete cell populations and dendritic laminae and thus are ideally suited for mediating lamina specific synapse development. Our first objective is to determine the contributions of LRRTM1 and LRRTM2 to lamina selective synapse development in the hippocampus. Our second objective is to dissect the molecular mechanism through which LRRTMs mediate synapse development. Finally, through in vivo manipulation, we propose to test whether synapse organizing proteins functioning through alternate pathways may restore defects in synaptic circuitry in mice lacking LRRTMs from birth. We expect that LRRTM1 and LRRTM2 are important for selective synapse development in hippocampal CA1 stratum radiatum and stratum lacunosum moleculare respectively and that they need to engage both presynaptic and postsynaptic binding partners to mediate bidirectional synapse development. Whereas lamination is a central organizing principle of both vertebrate and invertebrate brains, recent large scale screening projects point to the selective expression of adhesion proteins in defined cell populations and brain regions. Although this proposal will directly address the origins of synaptic specificity in the entorhinal cortex-CA1 and the CA3 Schaffer Collateral –CA1 synaptic pathways, the outcomes are expected to be representative of neural circuit formation generally and will thus be of great interest to the wider neuroscience community.