Distinct sets of FGF receptors sculpt excitatory and inhibitory synaptogenesis

Abstract

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.

Genetic insights into the mechanisms of Fgf signaling

“…Fgf7 primarily engages Fgfr2b, while Fgf22 can activate both Fgfr2b and Fgfr1b . Genetic disruption of Fgfr2b caused decreases in inhibitory and excitatory synapses, while loss of Fgfr1b prevented only excitatory synapse development (Dabrowski et al 2015). This supports the model that the differential presynaptic responses to each ligand are dependent on activation of distinct receptor profiles.…”

“…Loss of Fgf7 therefore causes increased seizure susceptibility, while loss of Fgf22 protects against seizures. The ability to induce different synapse identities is dependent on differences in each ligand's receptor affinity (Terauchi et al 2010;Dabrowski et al 2015). Fgf7 primarily engages Fgfr2b, while Fgf22 can activate both Fgfr2b and Fgfr1b .…”

Mechanisms of input and output synaptic specificity: finding partners, building synapses, and fine-tuning communication

“…FGF22 and FGF7 are released from CA3 dendrites and promote excitatory and inhibitory synapse formation, respectively [31–33]. FGFs localize to unique locations along the CA3 dendrite due to their co-transport with either excitatory or inhibitory postsynaptic proteins on separate kinesin motor proteins.…”

“…On the presynaptic side, input specificity is reinforced by different FGF receptors. In DG neurons, Fgfr2b and Fgfr1b are both required for FGF22 signaling, whereas in GABA neurons Fgfr2b but not Fgfr1b is required for FGF7 signaling [33]. Moreover, some of the downstream signaling mechanisms for building the presynaptic inputs are beginning to be elucidated for this pathway.…”

“…Moreover, some of the downstream signaling mechanisms for building the presynaptic inputs are beginning to be elucidated for this pathway. For example, Fgfr2b signals via FRS2 and P13K to promote excitatory synapse formation [33]. Future work will need to determine whether similar or unique signaling mechanisms mediate the construction of FGF-dependent inhibitory presynapses.…”