Abstract
Communication between pre- and postsynaptic cells promotes the initial organization of synaptic specializations, but subsequent synaptic stabilization requires transcriptional regulation. Here we show that fibroblast growth factor 22 (FGF22), a target-derived presynaptic organizer in the mouse hippocampus, induces the expression of insulin-like growth factor 2 (IGF2) for the stabilization of presynaptic terminals. FGF22 is released from CA3 pyramidal neurons and organizes the differentiation of excitatory nerve terminals formed onto them. Local application of FGF22 on the axons of dentate granule cells (DGCs), which are presynaptic to CA3 pyramidal neurons, induces IGF2 in the DGCs. IGF2, in turn, localizes to DGC presynaptic terminals and stabilizes them in an activity-dependent manner. IGF2 application rescues presynaptic defects of Fgf22(-/-) cultures. IGF2 is dispensable for the initial presynaptic differentiation, but is required for the following presynaptic stabilization both in vitro and in vivo. These results reveal a novel feedback signal that is critical for the activity-dependent stabilization of presynaptic terminals in the mammalian hippocampus.
Highlights
Synapses are the sites of neuronal communication in the brain
We find that i) target-derived fibroblast growth factor 22 (FGF22) signaling induces the expression of the insulin-like growth factor 2 (Igf2) gene in dentate granule cells (DGCs), ii) IGF2 localizes to presynaptic terminals of DGCs and stabilizes them, iii) the transportation of IGF2 to the presynaptic terminal is activity-dependent, and iv) IGF2 is not required for the initial presynaptic differentiation, but is required for subsequent presynaptic stabilization both in vitro and in vivo
We focused on genes expressed in DGCs, because they provide a major excitatory input to CA3 pyramidal neurons, and their presynaptic differentiation is dependent on FGF22–FGF receptors (FGFRs) signaling (Dabrowski et al, 2015)
Summary
Synapses are the sites of neuronal communication in the brain. Proper synapse formation is critical for appropriate brain function; aberrant synaptic connectivity may result in various neurological and psychiatric disorders, such as autism, Fragile X syndrome, epilepsy, and schizophrenia (Banerjee et al, 2014; Casillas-Espinosa et al, 2012; Lisman, 2012; Pfeiffer and Huber, 2009). Synapse formation begins with target recognition by axons, which is followed by synaptic differentiation at the contact sites. Synaptic differentiation is regulated by signals that are exchanged between pre- and postsynaptic sites.
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