Excitatory and inhibitory synaptogenesis by FGFs and their role in epilepsy

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DESCRIPTION (provided by applicant): Precise assembly of synapses is critical for proper functioning of the brain. Abnormal synapse formation or synaptic loss contributes to the progression of many neurological disorders. The goals of the research proposed here are to understand the molecular mechanisms underlying synapse formation in the brain and then use this information to develop new treatments for diseases resulting from synaptic malfunction. Synapses are formed by signaling between presynaptic and postsynaptic cells. Postsynaptic cell-derived "presynaptic organizers" promote local differentiation of presynaptic axons into functional nerve terminals at sites of synaptic contact. We performed an unbiased search for such presynaptic organizers and identified fibroblast growth factor 22 (FGF22), and its close relatives FGF7 and FGF10 as molecules that promote differentiation of presynaptic nerve terminals. In the brain, two major types of synapses, excitatory and inhibitory, need to be formed at their appropriate sites. An imbalance between excitatory and inhibitory synapses has been proposed to contribute to various neurological disorders including autism, schizophrenia, Tourette syndrome and epilepsy. We have recently found that FGF22 and FGF7 promote the organization of excitatory and inhibitory presynaptic terminals, respectively, as target-derived presynaptic organizers in the hippocampus. The differentiation of excitatory or inhibitory nerve terminals is specifically impaired in mutants lacking FGF22 or FGF7. As expected from the alterations in excitatory/inhibitory balance, FGF22 knockout (KO) mice are resistant and FGF7KO mice are prone to epileptic seizures. These results indicate that understanding the precise mechanisms of FGF-mediated excitatory and inhibitory synapse formation will lead to novel treatment strategies for epilepsy. Here we address (1) the mechanisms underlying the differential effects by FGF22 and FGF7 on excitatory and inhibitory presynaptic differentiation, (2) the signaling mechanisms that mediate the effects of FGFs, (3) physiological consequences of FGF deficiency in vivo, and (4) the role of FGFs in epileptogenesis. For these studies, we propose the following aims. Aim 1: Determine the in vivo localization of FGF22 and FGF7 and their dynamic distribution to distinct postsynaptic sites. Aim 2: Examine whether FGF22 and FGF7 signal through different FGF receptors and signaling pathways for their differential presynaptic effects. Aim 3: Delineate the functional consequences of FGF inactivation during brain development. Aim 4: Determine whether FGFs are involved in epileptic circuit formation during development or after brain insults. We will use an integrated combination of molecular genetic, cellular biological, biochemical, electrophysiological and imaging techniques to address these aims. It is anticipated that this study will reveal novel mechanisms underlying specific synapse formation and suggest novel strategies for treating brain disorders, such as epilepsy, that result from improper synapse formation. PUBLIC HEALTH RELEVANCE: The proposed research is aimed at understanding the molecular and cellular mechanisms of specific synapse formation in the brain. Specific synapse formation is critical for the proper functioning of the nervous system. The coordinated studies focus on the synaptogenic role of fibroblast growth factors (FGFs) and their differential effects on excitatory and inhibitory synapse formation in the hippocampus. We will specifically determine the role of FGFs in the pathogenesis of epilepsy, a disease with improper synaptic connections in the hippocampus. This body of work will allow us to determine the precise function and underlying mechanisms for FGFs in specific synapse formation, and help design appropriate strategies for the treatment and prevention of epilepsy.