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FGF acts as a co-transmitter through adenosine A2A receptor to regulate synaptic plasticity

Abstract

Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and depression. Adenosine, via activation of A2A receptors, antagonizes dopamine signaling at D2 receptors and A2A receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein–coupled A2A receptor (A2AR) and the receptor tyrosine kinase fibroblast growth factor receptor (FGFR). Concomitant activation of these two classes of receptors, but not individual activation of either one alone, caused a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity that was induced by a previously unknown A2AR/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A2A and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.

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Figure 1: Characterization of the physical interaction between A2ARs and FGFRs.
Figure 2: Characterization of the domains of interaction.
Figure 3: Synergistic activation of the MAPK pathway is induced by coactivation of A2ARs and FGFRs.
Figure 4: Synergistic activation of the MAPK pathway is reduced by an A2AR dominant-negative mutant.
Figure 5: CGS21680 and aFGF synergistically induce neurite formation in PC12 cells and increase spine density in primary neuronal cultures.
Figure 6: Coactivation of FGFRs and A2ARs facilitates the induction of LTP at corticostriatal synapses of striatopallidal MSNs.

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Acknowledgements

We are grateful to J. Rogers and H. Rebholz for critical reading of the manuscript, and to A. Nishi and G. Fisone for helpful discussions. This work was supported in part by grants from the US National Institutes of Health (MH074866 to P.G., A.C.N. and D.J.S., and NS34696 to D.J.S), the Simons Foundation, the Picower Foundation, and by award W81XWH-04-2-0009 from the US Medical Research and Materiel Command Neurotoxin Exposure Treatment Program to Intra-Cellular Therapies. M.F. was supported in part by a 2006 National Alliance for Research on Schizophrenia And Depression Young Investigator Award.

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Flajolet, M., Wang, Z., Futter, M. et al. FGF acts as a co-transmitter through adenosine A2A receptor to regulate synaptic plasticity. Nat Neurosci 11, 1402–1409 (2008). https://doi.org/10.1038/nn.2216

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