Pyridazine-derivatives Enhance Structural and Functional Plasticity of Tripartite Synapse Via Activation of Local...

Excitatory amino acid transporter 2 (EAAT2) is primarily located in perisynaptic astrocytic processes (PAP) where it plays a critical role in synaptic glutamate homeostasis. Dysregulation of EAAT2 at the translational level has been implicated in a myriad of neurological diseases. We previously discovered that pyridazine analogs can activate EAAT2 translation. Here, we sought to further refine the site and mechanism of compound action. We found that in vivo, compound treatment increased EAAT2 expression only in the PAP of astrocytes where EAAT2 mRNA also was identified. Direct application of compound to isolated PAP induced de novo EAAT2 protein synthesis, indicating that compound activates translation locally in the PAP. Using a screening process, we identified a set of PAP proteins that are rapidly up-regulated following compound treatment and a subset of these PAP proteins may be locally synthesized in the PAP. Importantly, these identified proteins are associated with the structural and functional capacity of the PAP, indicating compound enhanced plasticity of the PAP. Concomitantly, we found that pyridazine analogs increase synaptic protein expression in the synapse and enhance hippocampal long-term potentiation. This was not dependent upon compound-mediated local translation in neurons. This suggests that compound enhances the structural and functional capacity of the PAP which in turn facilitates enhanced plasticity of the tripartite synapse. Overall, this provides insight into the mechanism action site of pyridazine derivatives as well as the growing appreciation of the dynamic regulation and functional aspects of the PAP at the tripartite synapse.