Synergistic Regulation of Glutamatergic Transmission by Serotonin and Norepinephrine Reuptake Inhibitors in Prefrontal Cortical Neurons [Neurobiology]

July 23rd, 2014 by Yuen, E. Y., Qin, L., Wei, J., Liu, W., Liu, A., Yan, Z.

Monoamine system in prefrontal cortex (PFC) has been implicated in various mental disorders and has been the major target of anxiolytics and antidepressants. Clinical studies show that serotonin and norepinephrine reuptake inhibitors (SNRIs) produce better therapeutic effects than single selective reuptake inhibitors, while the underlying mechanisms are largely unknown. Here, we found that low-dose SNRIs, by acting on 5-HT1A and α2-adrenergic receptors (α2-AR) receptors, synergistically reduced AMPAR-mediated excitatory postsynaptic currents (EPSC) and AMPAR surface expression in PFC pyramidal neurons, via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs. The synergistic effect of SNRIs on AMPARs was blocked by inhibition of Activator of G protein Signaling 3 (AGS3), a G-protein modulator that prevents re-association of Gi protein α subunit and prolongs βγ-mediated signaling pathway. Moreover, the depression of AMPAR-EPSC by SNRIs required p38 kinase activity, which was increased by 5-HT1A and α2-AR co-activation in an AGS3-dependent manner. These results have revealed a potential mechanism for the synergy between serotonin and norepinephrine systems on the regulation of glutamatergic transmission in cortical neurons.
  • Posted in Journal of Biological Chemistry, Publications
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