FGF acts as a co-transmitter through adenosine A_2A receptor to regulate synaptic plasticity

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 A_2A receptors, antagonizes dopamine signaling at D2 receptors and A_2A receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein-coupled A_2A receptor (A_2AR) 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 A _2AR/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A_2A 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.