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.
Alterations in synaptic formation and plasticity have been implicated to a wide range of cognitive diseases in humans. Our studies focus on dissecting a novel synaptic adhesion pathway mediated by Latrophilins using a multidisciplinary approach, from molecular mechanisms to behavior. Importantly, polymorphisms in Latrophilin3 are strongly associated with ADHD. Therefore, we expect that these studies will provide important insight into a common, debilitating neurological disorder.
