Autophagy Induction Via κ‐Opioid Receptor is Implicated in Stress‐Driven Synaptic Alterations

Abstract

Neuronal autophagy controls the quality of cytoplasmic proteins through degradation of important synaptic proteins and modulates synaptic organization and morphogenesis (1). Evidence has shown that G protein coupled receptors are direct sensors regulating the autophagic machinery (2) and opioid receptors regulate neuronal plasticity and neurotransmission with as yet unclarified mechanism (3,4). Using in vitro and in vivo studies, we demonstrated that κ‐opioid receptor (κ‐OR) agonists induce autophagy via a PTX‐sensitive G protein manner and identified the downstream components involved (5). Our molecular analysis also revealed a κ‐OR‐driven upregulation of becn1 gene through ERK1,2‐dependent activation of the transcription factor CREB in neuronal cells. Moreover, our studies demonstrated that sub‐chronic U50,488H administration in mice causes profound increases of specific autophagic markers exclusively in the hippocampus with a concomitant decrease of several pre‐ and post‐synaptic proteins such as spinophilin, PSD‐95 and SNAP25. Finally, using acute stress, a stimulus known to increase the levels of the endogenous κ‐OR ligand dynorphin, we are demonstrating that administration of the κ‐ΟR selective antagonist, nor‐binaltorhimine, blocks the induction of autophagy and the stress‐evoked reduction of synaptic proteins in the hippocampus. These findings provide novel insights about the essential role of autophagic machinery into the mechanisms through which κ‐OR and its signaling regulates brain plasticity.