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Distinct FGFs promote differentiation of excitatory and inhibitory synapses

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 epilepsy1,2,3,4. Synapses are formed through communication between the appropriate synaptic partners5,6,7,8. 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.

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Figure 1: Expression of FGF22 and FGF7 in the hippocampal CA3 region during synapse formation at P8.
Figure 2: Specific defects in excitatory or inhibitory presynaptic differentiation in CA3 of FGF22KO and FGF7KO mice.
Figure 3: Target-derived FGF22 and FGF7 selectively promote differentiation of glutamatergic or GABAergic presynaptic terminals in CA3 through distinct localization and signalling pathways.
Figure 4: Altered synaptic transmission and seizure susceptibility in FGFKO mice, and a model for the role of FGF22 and FGF7 in specific presynaptic differentiation.

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Acknowledgements

We thank J. Sanes and M. Hortsch for critical comments on the manuscript; M. Webb and P. Woodhams for the antibody Py; D. Sorenson for help with electron microscopy; A. Murayama for plasmid construction; M. De Freitas for help with histology; and M. Zhang for technical assistance. This work was supported by the Ester A. & Joseph Klingenstein Fund, the Edward Mallinckrodt Jr Foundation, the March of Dimes Foundation and the Whitehall Foundation (H.U.).

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A.T. and H.U. conceived and designed the experiments, performed or participated in each of the experiments and wrote the manuscript. E.M.J.-V. and M.A.S. performed the electrophysiological recordings. A.B.T. participated in the culture and histological experiments. D.J. performed the seizure-related experiments.

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Correspondence to Hisashi Umemori.

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The authors declare no competing financial interests.

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Terauchi, A., Johnson-Venkatesh, E., Toth, A. et al. Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature 465, 783–787 (2010). https://doi.org/10.1038/nature09041

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