Fibroblast Growth Factor Receptors Sculpt Excitatory and Inhibitory Synapses in the Hippocampal Neural Circuit

The brain consists of a complex network of interconnected neurons that underlie stimulus processing and response, thoughts, and emotions. In order for the brain to function properly, neurons must appropriately connect with each other through synapses. Synapse development has many challenges: synapses must form between appropriate synaptic partners; functionality requires the assembly of complex molecular machinery both presynaptically (in the axon terminal) and postsynaptically (in the dendrite); and specific synapses, for example excitatory versus inhibitory, must develop concurrently throughout the brain. Defective synapse formation can result in neurological diseases, such as schizophrenia, autism, or epilepsy. Healthy synaptogenesis requires multiple levels of molecular control. One set of molecular cues guiding presynaptic differentiation at specific synapses are FGF22 and FGF7, which are secreted from dendrites of CA3 pyramidal neurons in the hippocampus: FGF22 induces synaptic vesicle accumulation in excitatory axon terminals, and FGF7 induces synaptic vesicle accumulation in inhibitory axon terminals (Terauchi et al., 2010). Significantly, animals lacking either FGF have altered susceptibility to epileptic seizures (Terauchi et al., 2010), underscoring the importance of developing a neural circuit with appropriate excitatory-inhibitory balance. The mechanisms through which FGF22 and FGF7 induce specific presynaptic differentiation were previously unknown. Here, I present my work addressing FGF receptors (FGFRs) and their role in FGF22- and FGF7-induced presynaptic differentiation: FGFR2b and FGFR1b are required for FGF22 to induce excitatory presynaptic differentiation, and FGFR2b for FGF7 to induce inhibitory presynaptic differentiation. FGFR2b and FGFR1b are functionally required in dentate granule cells (excitatory presynaptic input to CA3) and FGFR2b is functionally required in interneurons (inhibitory presynaptic input). FGFR2b utilizes intracellular signaling downstream of FRS2 and PI3K to induce excitatory presynaptic differentiation in response to FGF22, but signaling downstream of PLCgamma is not required (Dabrowski et al., 2015). Thus, distinct sets of FGFRs are required for FGF-dependent excitatory and inhibitory presynaptic differentiation, and utilize precise downstream signaling pathways. Finally, I describe a novel aspect of FGF22 function in controlling dendritic spine density in dentate granule cells. My work provides important insights into excitatory and inhibitory synapse formation. Ultimately, synaptogenic FGFRs may provide a novel therapeutic target in neuropsychiatric disease.PhDNeuroscience PhDUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/136928/1/adabrows_1.pd