Buttressing a balanced brain: Target-derived FGF signaling regulates excitatory/inhibitory tone and adult neurogenesis within the maturating hippocampal network

Abstract

Brain development involves multiple levels of molecular coordination in forming a functional nervous system. The hippocampus is a brain area that is important for memory formation and spatial reasoning. During early postnatal development of the hippocampal circuit, Fibroblast growth factor 22 (FGF22) and FGF7 act to establish a balance of excitatory and inhibitory tone. Both FGFs are secreted from CA3 dendrites, acting on excitatory or inhibitory axon terminals formed onto CA3 dendrites, respectively. Mechanistically, FGF22 utilizes FGFR2b and FGFR1b to induce synaptic vesicle recruitment within axons of dentate granule cells (DGCs), and FGF7 utilizes FGFR2b to induce synaptic vesicle recruitment within interneuron axons. FGF signaling eventually induces gene expression in the presynaptic neurons; however, the effects of FGF22-induced gene expression within DGCs and FGF7-induced gene expression within interneurons in the context of a developing hippocampal circuit have yet to be explored. Here, we propose one hypothetical mechanism of FGF22-induced gene expression in controlling adult neurogenesis.

Keywords: FGF22; FGF7; FGFR1b; FGFR2b; Fibroblast growth factor receptors; adult neurogenesis; excitatory/inhibitory; hippocampus; presynaptic differentiation; synapse development.

Figure 1.

Target-derived FGFs induce excitatory and inhibitory presynaptic differentiation. Top: In the hippocampal circuit, dentate granule cells (DGCs) provide a major excitatory input to the CA3, and interneurons provide the inhibitory input. Bottom: FGF22 and FGF7 are secreted at excitatory and inhibitory nascent synapses on CA3 dendrites in the hippocampus. FGF22 acts on FGFR2b and FGFR1b within DGCs to induce synaptic vesicle accumulation in excitatory axon terminals, and FGF7 acts on FGFR2b within interneurons to induce synaptic vesicle accumulation within inhibitory axoN-terminals. FGFR2b activated by FGF22 utilizes kinase activity and signaling downstream of FRS2 and PI3K, but not PLC-gamma, to induce accumulation of excitatory synaptic vesicles.

Figure 2.

A model for the control of adult neurogenesis in the dentate gyrus by CA3-derived FGF22. One potential effect of CA3-derived FGF22, in addition to excitatory presynaptic differentiation, may be the regulation of adult neurogenesis in the dentate gyrus, thus balancing levels of adult neurogenesis with the potential for excitatory synapse formation in the CA3. Top: During the first postnatal week, FGF22 is highly expressed in the CA3 and induces excitatory presynaptic differentiation. FGF22 activates FGFR2b and FGFR1b in DGCs to induce presynaptic differentiation. Middle: FGF22 induces gene expression in DGCs, some of which encode for secreted and extracellular factors implicated in control of adult neurogenesis (unpublished data) through sculpting the developing subgranular zone (SGZ) neurogenic niche. Bottom: We hypothesize that gene expression induced by CA3-derived FGF22 regulates adult neurogenesis, through secreted factors influencing the SGZ neurogenic niche. Indeed, FGF22KO mice have decreased adult neurogenesis.