Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis.
Neurons in the brain must establish a balanced network of excitatory and inhibitory synapses during development for the brain to function properly. An imbalance between these synapses underlies various neurological and psychiatric disorders. The formation of excitatory and inhibitory synapses requires precise molecular control. In the hippocampus, the structure crucial for learning and memory, fibroblast growth factor 22 (FGF22) and FGF7 specifically promote excitatory or inhibitory synapse formation, respectively. Knockout of either Fgf gene leads to excitatory-inhibitory imbalance in the mouse hippocampus and manifests in an altered susceptibility to epileptic seizures, underscoring the importance of FGF-dependent synapse formation. However, the receptors and signaling mechanisms by which FGF22 and FGF7 induce excitatory and inhibitory synapse differentiation are unknown. Here, we show that distinct sets of overlapping FGF receptors (FGFRs), FGFR2b and FGFR1b, mediate excitatory or inhibitory presynaptic differentiation in response to FGF22 and FGF7. Excitatory presynaptic differentiation is impaired in Fgfr2b and Fgfr1b mutant mice; however, inhibitory presynaptic defects are only found in Fgfr2b mutants. FGFR2b and FGFR1b are required for an excitatory presynaptic response to FGF22, whereas only FGFR2b is required for an inhibitory presynaptic response to FGF7. We further find that FGFRs are required in the presynaptic neuron to respond to FGF22, and that FRS2 and PI3K, but not PLCγ, mediate FGF22-dependent presynaptic differentiation. Our results reveal the specific receptors and signaling pathways that mediate FGF-dependent presynaptic differentiation, and thereby provide a mechanistic understanding of precise excitatory and inhibitory synapse formation in the mammalian brain.
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Ania
A
Dabrowski
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Akiko
A
Terauchi
Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Cameron
C
Strong
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA hisashi.umemori@childrens.harvard.edu.
Hisashi
H
Umemori
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
C476387:Fgf22 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2
Excitatory-inhibitory balance; Fibroblast growth factor receptor; Hippocampus; Mouse; Receptor tyrosine kinase signaling; Synapse formation