Abstract
The differential formation of excitatory (glutamate-mediated) and inhibitory (GABA-mediated) synapses is a critical step for the proper functioning of the brain. An imbalance in these synapses may lead to various neurological disorders such as autism, schizophrenia, Tourette's syndrome and epilepsy. Synapses are formed through communication between the appropriate synaptic partners. However, the molecular mechanisms that mediate the formation of specific synaptic types are not known. Here we show that two members of the fibroblast growth factor (FGF) family, FGF22 and FGF7, promote the organization of excitatory and inhibitory presynaptic terminals, respectively, as target-derived presynaptic organizers. FGF22 and FGF7 are expressed by CA3 pyramidal neurons in the hippocampus. The differentiation of excitatory or inhibitory nerve terminals on dendrites of CA3 pyramidal neurons is specifically impaired in mutants lacking FGF22 or FGF7. These presynaptic defects are rescued by postsynaptic expression of the appropriate FGF. FGF22-deficient mice are resistant to epileptic seizures, and FGF7-deficient mice are prone to them, as expected from the alterations in excitatory/inhibitory balance. Differential effects of FGF22 and FGF7 involve both their distinct synaptic localizations and their use of different signalling pathways. These results demonstrate that specific FGFs act as target-derived presynaptic organizers and help to organize specific presynaptic terminals in the mammalian brain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation*
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Cells, Cultured
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Dendrites / metabolism
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Disease Susceptibility
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Epilepsy / chemically induced
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Epilepsy / genetics
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Epilepsy / physiopathology
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Excitatory Postsynaptic Potentials / physiology*
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Fibroblast Growth Factor 7 / deficiency
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Fibroblast Growth Factor 7 / genetics
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Fibroblast Growth Factor 7 / metabolism*
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Fibroblast Growth Factors / deficiency
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / metabolism*
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Gene Expression Profiling
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Glutamic Acid / metabolism
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Hippocampus / cytology
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Hippocampus / embryology
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Hippocampus / metabolism
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Hippocampus / pathology
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In Situ Hybridization
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Inhibitory Postsynaptic Potentials / physiology*
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Kindling, Neurologic
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Mice
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Mice, Knockout
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Miniature Postsynaptic Potentials / physiology
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Presynaptic Terminals / classification
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Presynaptic Terminals / metabolism
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Presynaptic Terminals / pathology
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Presynaptic Terminals / ultrastructure
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Pyramidal Cells / cytology
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Pyramidal Cells / metabolism
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Pyramidal Cells / pathology
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Receptors, Fibroblast Growth Factor / metabolism
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Seizures / chemically induced
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Seizures / genetics
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Seizures / radiotherapy
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Synapses / classification*
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Synapses / metabolism*
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Synapses / pathology
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Synapses / ultrastructure
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Synaptic Transmission
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Synaptic Vesicles / metabolism
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Synaptic Vesicles / pathology
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Synaptic Vesicles / ultrastructure
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gamma-Aminobutyric Acid / metabolism
Substances
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Fgf22 protein, mouse
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Fgf7 protein, mouse
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Receptors, Fibroblast Growth Factor
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Fibroblast Growth Factor 7
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Glutamic Acid
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gamma-Aminobutyric Acid
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Fibroblast Growth Factors