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Distinct FGFs promote differentiation of excitatory and inhibitory synapses


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.


  1. Rubenstein, J. L. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003)

    Article  CAS  PubMed Central  Google Scholar 

  2. Wassef, A., Baker, J. & Kochan, L. D. GABA and schizophrenia: a review of basic science and clinical studies. J. Clin. Psychopharmacol. 23, 601–640 (2003)

    Article  CAS  PubMed Central  Google Scholar 

  3. Singer, H. S. & Minzer, K. Neurobiology of Tourette’s syndrome: concepts of neuroanatomic localization and neurochemical abnormalities. Brain Dev. 25, S70–S84 (2003)

    Article  PubMed Central  Google Scholar 

  4. Möhler, H. GABAA receptors in central nervous system disease: anxiety, epilepsy, and insomnia. J. Recept. Signal Transduct. Res. 26, 731–740 (2006)

    Article  PubMed Central  Google Scholar 

  5. Sanes, J. R. & Lichtman, J. W. Development of the vertebrate neuromuscular junction. Annu. Rev. Neurosci. 22, 389–442 (1999)

    CAS  PubMed  Google Scholar 

  6. Fox, M. A. & Umemori, H. Seeking long-term relationship: axon and target communicate to organize synaptic differentiation. J. Neurochem. 97, 1215–1231 (2006)

    Article  CAS  PubMed Central  Google Scholar 

  7. Waites, C. L., Craig, A. M. & Garner, C. C. Mechanisms of vertebrate synaptogenesis. Annu. Rev. Neurosci. 28, 251–274 (2005)

    Article  CAS  PubMed Central  Google Scholar 

  8. Dalva, M. B., McClelland, A. C. & Kayser, M. S. Cell adhesion molecules: signalling functions at the synapse. Nature Rev. Neurosci. 8, 206–220 (2007)

    Article  CAS  Google Scholar 

  9. Umemori, H., Linhoff, M. W., Ornitz, D. M. & Sanes, J. R. FGF22 and its close relatives are presynaptic organizing molecules in the mammalian brain. Cell 118, 257–270 (2004)

    Article  CAS  Google Scholar 

  10. Fox, M. A. et al. Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell 129, 179–193 (2007)

    Article  CAS  Google Scholar 

  11. Guo, L., Degenstein, L. & Fuchs, E. Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev. 10, 165–175 (1996)

    Article  CAS  PubMed Central  Google Scholar 

  12. Steward, O. & Falk, P. M. Selective localization of polyribosomes beneath developing synapses: a quantitative analysis of the relationships between polyribosomes and developing synapses in the hippocampus and dentate gyrus. J. Comp. Neurol. 314, 545–557 (1991)

    Article  CAS  PubMed Central  Google Scholar 

  13. Danglot, L., Triller, A. & Marty, S. The development of hippocampal interneurons in rodents. Hippocampus 16, 1032–1060 (2006)

    Article  CAS  PubMed Central  Google Scholar 

  14. Gonzalez, A. M., Berry, M., Maher, P. A., Logan, A. & Baird, A. A comprehensive analysis of the distribution of FGF-2 and FGFR1 in the rat brain. Brain Res. 701, 201–226 (1995)

    Article  CAS  PubMed Central  Google Scholar 

  15. Zhang, X. et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J. Biol. Chem. 281, 15694–15700 (2006)

    Article  CAS  PubMed Central  Google Scholar 

  16. Woodhams, P. L., Webb, M., Atkinson, D. J. & Seeley, P. J. A monoclonal antibody, Py, distinguishes different classes of hippocampal neurons. J. Neurosci. 9, 2170–2181 (1989)

    Article  CAS  PubMed Central  Google Scholar 

  17. Xiao, M. et al. Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14. Mol. Cell. Neurosci. 34, 366–377 (2007)

    Article  CAS  PubMed Central  Google Scholar 

  18. Morimoto, K., Fahnestock, M. & Racine, R. J. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog. Neurobiol. 73, 1–60 (2004)

    Article  CAS  PubMed Central  Google Scholar 

  19. Racine, R. J. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 32, 281–294 (1972)

    Article  CAS  PubMed Central  Google Scholar 

  20. Umemori, H. & Sanes, J. R. Signal regulatory proteins (SIRPS) are secreted presynaptic organizing molecules. J. Biol. Chem. 283, 34053–34061 (2008)

    Article  CAS  PubMed Central  Google Scholar 

  21. Linhoff, M. W. et al. An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron 61, 734–749 (2009)

    Article  CAS  PubMed Central  Google Scholar 

  22. Lin, Y. et al. Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 455, 1198–1204 (2008)

    Article  ADS  CAS  PubMed Central  Google Scholar 

  23. Gibson, J. R., Huber, K. M. & Südhof, T. C. Neuroligin-2 deletion selectively decreases inhibitory synaptic transmission originating from fast-spiking but not from somatostatin-positive interneurons. J. Neurosci. 29, 13883–13897 (2009)

    Article  CAS  PubMed Central  Google Scholar 

  24. Schaeren-Wiemers, N. & Gerfin-Moser, A. A. single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 100, 431–440 (1993)

    Article  CAS  Google Scholar 

  25. Goslin, K., Asmussen, H. & Banker, G. in Culturing Nerve Cells (eds Banker, G. & Goslin, K.) 339–370 (MIT Press, 1998)

    Google Scholar 

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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).

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