Investigating the neuronal function of mammalian Latrophilins, candidate synaptic adhesion molecules implicated in ADHD.

 描述（由申请人提供）：正确的神经回路功能和行为需要在正确的突触伴侣之间建立连接，维持连接，并消除不相关的突触。越来越多的证据表明，突触细胞粘附分子是突触形成所必需的。然而，突触形成的普遍方面所必需的分子，以及体内突触连接的显着多样性和特异性的分子，仍有待阐明。哺乳动物latrophilins（Lphn 1，2和3）是粘附型GPCR最近出现的候选突触细胞粘附分子通过异嗜性结合到teneurin和FLRT。Lphn在哺乳动物脑中高度富集，并且Lphn 1和3在脑中突触发生的大量时期期间瞬时上调。Lphns在脊椎动物和无脊椎动物中也高度保守，这表明它们可能介导突触发育的普遍方面。此外，Lphn 3的多态性与ADHD相关，表明Lphn 3调节信息加工。尽管Lphns具有这些迷人的特性，但它们在神经系统中的精确生物学作用仍然难以捉摸。我们建议通过询问Lphn组成型和条件性KO小鼠与病毒介导的神经元示踪，组织学，电生理学和行为来研究Lphns的神经元功能。此外，我们将阐明Lphn神经元功能的分子机制，使用Lphn结构/功能突变体，包括与ADHD相关的多态性。这些研究将提供深入了解神经元粘附，突触发育，和一个共同的人类神经系统疾病。

 DESCRIPTION (provided by applicant): Proper neural circuit function and behavior requires the establishment of connections between correct synaptic partners, maintenance of connections, and elimination of irrelevant synapses. Increasing evidence suggests that synaptic cell-adhesion molecules are essential for synapse formation. However, molecules essential for universal aspects of synapse formation, as well as molecules underlying the remarkable diversity and specificity of synaptic connections in vivo, remain to be elucidated. Mammalian latrophilins (Lphn1, 2, and 3) are adhesion-type GPCRs that have recently emerged as candidate synaptic cell adhesion molecules by heterophilic binding to teneurins and FLRTs. Lphns are highly enriched in the mammalian brain, and Lphn1 and 3 are transiently upregulated during the massive period of synaptogenesis in the brain. Lphns are also highly conserved across vertebrates and invertebrates, suggesting they may mediate universal aspects of synapse development. Moreover, polymorphisms in Lphn3 are correlated with ADHD, suggesting that Lphn3 regulates information processing. Despite these fascinating properties of Lphns, their precise biological roles in the nervous system remain elusive. We propose to investigate the neuronal function of Lphns by interrogating Lphn constitutive and conditional KO mice with viral-mediated neuronal tracing, histology, electrophysiology, and behavior. Furthermore, we will elucidate the molecular mechanisms of Lphn neuronal function using Lphn structure/function mutants, including polymorphisms associated with ADHD. These studies will provide insight into neuronal adhesion, synapse development, and a common human neurological disorder.