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. 2010 Jun 10;465(7299):783-7.
doi: 10.1038/nature09041. Epub 2010 May 26.

Distinct FGFs promote differentiation of excitatory and inhibitory synapses

Akiko Terauchi  1 , Erin M Johnson-Venkatesh, Anna B Toth, Danish Javed, Michael A Sutton, Hisashi Umemori
Affiliations

Distinct FGFs promote differentiation of excitatory and inhibitory synapses

Akiko Terauchi et al. Nature. .

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.

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Figures

Figure 1
Figure 1. Expression of FGF22 and FGF7 in the hippocampal CA3 region during synapse formation (P8)
a, fgf22 and fgf7 mRNAs are highly expressed in CA3 pyramidal neurons (arrowheads), but not in CA1 pyramidal neurons. Bottom panels are negative controls using FGFKO sections. b, fgfr2 mRNA is widely expressed throughout the hippocampus. c, FGF22 and FGF7 proteins are localized in CA3 synapse-rich areas. Pictured areas correspond to the boxed area in a. Scale bars, 500 μm (a, b) and 50 μm (c). SR: stratum radiatum, SL: stratum lucidum.
Figure 2
Figure 2. Specific defects in excitatory or inhibitory presynaptic differentiation in CA3 of FGF22KO and FGF7KO mice
a, SV2 staining in CA1 and CA3 from P14 WT, FGF22KO and FGF7KO mice demonstrates decreased synaptic vesicle (SV) clustering in CA3 of FGFKO mice. b, Normal active zone formation (bassoon clustering) in CA3 of FGFKO mice. c, d, Staining in CA3 for VGLUT1 (c) and VGAT (d), showing impaired glutamatergic and GABAergic SV clustering in CA3 of FGF22KO and FGF7KO mice, respectively. e, Normal PSD95 and gephyrin clustering in CA3 of FGFKO mice. f–k, Electron microscopic (EM) analysis of asymmetric (excitatory, f–h) and symmetric (inhibitory, i–k) synapses in CA3. Synaptic density (x1,000/mm2, f, i), representative synapses (g, j), and analysis of SVs within 400 nm from the active zone (AZ; h, k) show specific presynaptic defects in FGFKO mice. l, Western blotting of CA3 lysates, indicating no overall change in synaptic protein expression in FGFKO mice. Error bars are s.e.m. Staining data are from 15–126 fields from 5–14 mice. EM data are from 5–20 synapses. Significant difference from control at *P < 0.05; **P < 0.01; ***P < 0.001, ANOVA followed by Tukey test. Scale bars, 20 μm (c, d) and 200 nm (g, j).
Figure 3
Figure 3. Target-derived FGF22 and FGF7 selectively promote differentiation of glutamatergic or GABAergic presynaptic terminals in CA3 through distinct localization and signaling pathways
a, VGLUT1 and VGAT clustering on FGF-transfected WT hippocampal neurons (labeled with GFP; 7 DIV). b, Defects in the clustering of VGLUT1 and VGAT on the dendrites of FGF22KO or FGF7KO CA3 pyramidal neurons (Py-positive; 14 DIV). The number (puncta/mm neurite) and size of puncta were quantified. c, The number (x1,000 puncta/mm2) and size of VGLUT1 and VGAT puncta on non-CA3 pyramidal neurons (Py-negative). d, The presynaptic defects in FGFKO cultures are rescued by expression of the corresponding FGF in postsynaptic CA3 pyramidal neurons. Data are normalized to WT. e, f, FGF22-EGFP localizes to glutamatergic, and FGF7-DsRed to GABAergic synapses (arrowheads). g, Endogenous FGF22 and FGF7 are colocalized with PSD95 or VGAT. h, FGF22-EGFP and FGF7-DsRed exhibit differential dendritic localization. i, j, The number (x1,000 puncta/mm2) and size of VGLUT1 (i) or VGAT (j) puncta after FGF bath application to WT cultures. k, VGLUT1 and VGAT staining intensity of control and FGFR2KO CA3 sections (P8). l, Normalized staining intensity of FGFR2KO sections. Error bars are s.e.m. Data are from 50–290 neurites or 8–66 fields from at least three experiments. Significant difference from control at *P < 0.05; **P < 0.01; ***P < 0.001, t-test (d, k, l) or ANOVA followed by Tukey test; #P=0.073 (i). Scale bars, 10 μm.
Figure 4
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
a–d, Representative whole-cell recordings of mEPSCs (a) and mIPSCs (c) from WT and FGFKO hippocampal neurons; frequency and amplitude of mEPSCs (b) and mIPSCs (d) in the indicated groups (18–24 neurons/group). e, Representative time-course of seizure development during kindling experiments. f, Percentage of mice kindled when about half of the control mice are kindled (~21 PTZ injections) from four independent experiments (4–6 mice/experiment). Error bars are s.e.m. Significant difference from control at *P < 0.05 and ***P < 0.001, ANOVA followed by Tukey test. g, Summary model. FGF22 and FGF7 from CA3 pyramidal neurons promote the differentiation of excitatory and inhibitory presynaptic terminals, respectively. FGF22 and FGF7 are localized at corresponding synapses and activate differential signaling pathways for specific presynaptic differentiation.
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