Latrophilin Function in Synapse Formation

Neural circuits are constructed by synapses that connect neurons into vast networks. Although many neural circuits have been characterized, the molecular and cellular mechanisms that build their synaptic architecture remain largely unknown. During synapse formation that establishes the synaptic architecture of neural circuits, bi-directional signaling via trans-synaptic adhesion molecules is thought to control assembly of synapses. Strikingly, genetic changes in trans-synaptic adhesion molecules often predispose to neuropsychiatric disorders, suggesting that dysfunction of the synaptic architecture of neural circuits contributes to neuropsychiatric disorders, although the nature of these impairments is poorly understood. Our preliminary data show that in hippocampal neurons, formation of subsets of excitatory synapses requires latrophilins (Lphns), a family of three postsynaptic adhesion-GPCRs. Different Lphns mediate establishment of distinct synapses even in the same neuron, suggesting that they are involved not only in constructing synapses, but also in determining their specificity. How Lphns mediate synapse formation, and to what extent their synapse-formation function involves GPCR signaling or adhesive interactions, remains unknown. Moreover, SNPs in the human Lphn3 gene (ADGRL3) downregulate Lphn3 expression robustly. The present application proposes to examine the signaling mechanisms that mediate Lphn-dependent synapse formation, to explore how Lphns determine synapse specificity, and to investigate how changes in Lphn3 expression change synaptic function. Specifically, the proposed experiments will test the overall hypotheses that (1) Lphns control synapse formation and maintenance by a GPCR-mediated mechanism involving locally restricted signaling, that (2) different Lphn isoforms control formation of distinct synapses via sequence-specific differences in their protein interactions and GPCR function, and that (3) changes in Lphn3 expression impair formation of a specific subset of synapses. Three Specific Aims will test these hypotheses, thus targeting key questions that are most relevant for understanding how neural circuits are wired and how impairment of neural circuits alter cognition. Using both mouse and human neurons as a model system, the project will pursue broadly interdisciplinary approaches in both mice and human neurons that range from biophysical studies of ligand-receptor complexes to cell-biological investigations of intracellular signaling to behavioral studies probing for cognitive changes. Thereby, this application will provide insight into how Lphns drive synapse formation in mice, and how decreased expression of Lphn3 predisposes to synaptic changes in human neurons. Addressing these questions is of paramount interest in basic and translational neuroscience because neural circuits that process the brain’s information are constructed by synapse formation, and dysfunction or imbalance of synaptic communication in neural circuits likely underlies the pathogenesis of neuropsychiatric disorders.