Abstract
Various growth factors regulate synapse development and neurogenesis, and are essential for brain function. Changes in growth factor signaling are implicated in many neuropsychiatric disorders such as depression, autism and epilepsy. We have previously identified that fibroblast growth factor 22 (FGF22) is critical for excitatory synapse formation in several brain regions including the hippocampus. Mice with a genetic deletion of FGF22 (FGF22 null mice) have fewer excitatory synapses in the hippocampus. We have further found that as a behavioral consequence, FGF22 null mice show a depression-like behavior phenotype such as increased passive stress-coping behavior and anhedonia, without any changes in motor, anxiety, or social cognitive tests, suggesting that FGF22 is specifically important for affective behavior. Thus, addressing the precise roles of FGF22 in the brain will help understand how synaptogenic growth factors regulate affective behavior. In the hippocampus, FGF22 is expressed mainly by CA3 pyramidal neurons, but also by a subset of dentate granule cells. We find that in addition to synapse formation, FGF22 also contributes to neurogenesis in the dentate gyrus: FGF22 null mice show decreased dentate neurogenesis. To understand the cell type-specific roles of FGF22, we generated and analyzed CA3-specific FGF22 knockout mice (FGF22-CA3KO). We show that FGF22-CA3KO mice have reduced excitatory synapses on CA3 pyramidal neurons, but do not show changes in dentate neurogenesis. Behaviorally, FGF22-CA3KO mice still show increased immobility and decreased latency to float in the forced swim test and decreased preference for sucrose in the sucrose preference test, which are suggestive of a depressive-like phenotype similar to FGF22 null mice. These results demonstrate that: (i) CA3-derived FGF22 serves as a target-derived excitatory synaptic organizer in CA3 in vivo; (ii) FGF22 plays important roles in dentate neurogenesis, but CA3-derived FGF22 is not involved in neurogenesis; and (iii) a depression-like phenotype can result from FGF22 inactivation selectively in CA3 pyramidal neurons. Our results link the role of CA3-derived FGF22 in synapse development, and not in neurogenesis, to affective behavior.
Highlights
Growth factor signaling is implicated in many aspects of brain development and function
Since Fgf22 expression in control mice was highest in the CA3a and CA3b subregions (Figures 1A,B), we focused on these subregions for the analysis of synapses
In order to investigate whether CA3-derived Fibroblast Growth Factor 22 (FGF22) is necessary for excitatory presynaptic differentiation in CA3, we evaluated the clustering of excitatory synaptic vesicles by staining for VGLUT1, which is on the excitatory synaptic vesicles
Summary
Growth factor signaling is implicated in many aspects of brain development and function. We proposed that FGF22 serves as a target (postsynaptic neuron)-derived presynaptic organizer in the hippocampus, because, using cultured neurons, we found: (i) FGF22 overexpression induced excitatory synapses on the FGF22 expressing neurons; and (ii) postsynaptic expression of FGF22 rescued impaired excitatory synapse formation in cultures prepared from FGF22 null mice (Terauchi et al, 2010). This idea has not been tested in vivo. In this article, we ask whether FGF22 acts as a target-derived presynaptic organizer in vivo using mice in which FGF22 is selectively inactivated in CA3 pyramidal neurons, where FGF22 is highly expressed during development
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