The Role of κ‐Opioid Receptor‐Induced Autophagy in Synaptic Alterations

Abstract

Autophagy is a lysosomal degradation pathway that eliminates misfolded proteins and dysfunctional organelles to safeguard cellular homeostasis. In neurons, autophagy controls the quality of cytoplasmic proteins through degradation of important synaptic proteins and modulates synaptic organization and morphogenesis (1). Emerging studies have shown that G protein coupled receptors (GPCRs) are direct sensors regulating the autophagic machinery (2) and that opioid receptors regulate neurogenesis and neurotransmission with as yet unclarified mechanisms (3, 4). In this regard, we have recently demonstrated that κ‐opioid receptor (κ‐OR) agonists induce autophagy in neuronal cells in vitro via a PTX‐sensitive G protein mechanism and identified the downstream components involved in this process (5, 6). However, it is unknown whether κ‐OR agonists also mediate these effects in vivo and, specifically, whether opiodergic alterations mediated by selective opioid receptor agonists may control synaptic function and spine morphology through autophagy induction.We are now reporting by in vivo studies that brain extracts obtained from mice that have been treated with the κ‐OR selective agonist U‐50,488H display profound increases of specific autophagic markers. This κ‐OR induced autophagy increase is region‐specific and detected only in the hippocampal extracts. Moreover, isolated synaptosomes from saline‐ or U50,488H‐treated mice exhibited a profound decrease of a number of essential neuronal proteins enriched in dendritic spines, suggesting that these proteins are engulfed in the κ‐OR‐induced autophagic cargo. Our results demonstrate for the first time that κ‐OR‐induced autophagy plays a key role in synaptic function and dendritic spine density and may contribute to the mood disorders targeted by the dynorphin‐κ‐OR system.Support or Funding InformationThis work was supported by the GSRT Excellence II 3722 ‐”NO‐ALGOS” to Z.G; the SANITURA (MIS 5002514) grant, implemented under the Action for the Strategic Development on the Research and Technological Sectors & the OPENSCREEN‐GR “An Open‐Access Research Infrastructure of Chemical Biology and Target‐Based Screening Technologies for Human and Animal Health, Agriculture and the Environment” (MIS 5002691) funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020).