Morphine Withdrawal Modifies Prion Protein Expression in Rat Hippocampus.

Vincenzo Mattei,Valeria Manganelli,Sergio Scaccianoce,Maurizio Sorice,Francesca Santilli,Tina Garofalo,Roberta Misasi,Stefano Martellucci,Niccolò Candelise,Alessandra Caruso,Victoria Lawson

doi:10.1371/journal.pone.0169571

Abstract

The hippocampus is a vulnerable brain structure susceptible to damage during aging and chronic stress. Repeated exposure to opioids may alter the brain so that it functions normally when the drugs are present, thus, a prolonged withdrawal might lead to homeostatic changes headed for the restoration of the physiological state. Abuse of morphine may lead to Reacting Oxygen Species-induced neurodegeneration and apoptosis. It has been proposed that during morphine withdrawal, stress responses might be responsible, at least in part, for long-term changes of hippocampal plasticity. Since prion protein is involved in both, Reacting Oxygen Species mediated stress responses and synaptic plasticity, in this work we investigate the effect of opiate withdrawal in rats after morphine treatment. We hypothesize that stressful stimuli induced by opiate withdrawal, and the subsequent long-term homeostatic changes in hippocampal plasticity, might modulate the Prion protein expression. Our results indicate that abstinence from the opiate induced a time-dependent and region-specific modification in Prion protein content, indeed during morphine withdrawal a selective unbalance of hippocampal Prion Protein is observable. Moreover, Prion protein overexpression in hippocampal tissue seems to generate a dimeric structure of Prion protein and α-cleavage at the hydrophobic domain. Stress factors or toxic insults can induce cytosolic dimerization of Prion Protein through the hydrophobic domain, which in turn, it stimulates the α-cleavage and the production of neuroprotective Prion protein fragments. We speculate that this might be the mechanism by which stressful stimuli induced by opiate withdrawal and the subsequent long-term homeostatic changes in hippocampal plasticity, modulate the expression and the dynamics of Prion protein.

Highlights

Prion protein (PrPC) is a glycosylphosphatidylinositol (GPI) anchored protein found in the outer leaflet of the plasma membrane [1]
In a first series of experiments, we investigated the effects of both acute and chronic morphine exposure on PrPC expression in rats hippocampus and prefrontal cortex
PrPC expression in the prefrontal cortex was unaffected by morphine withdrawal (Fig 3C)

Summary

Introduction

Prion protein (PrPC) is a glycosylphosphatidylinositol (GPI) anchored protein found in the outer leaflet of the plasma membrane [1]. Like many GPI-anchored protein, PrPC is found in sphingolipid-rich membrane microdomains known as lipid raft [3,5] and, beyond them, into post-synaptic densities [6]. This membrane-bound isoform dimerizes and can act as cell surface receptor, as a co-receptor, or form multimolecular complexes and recruit downstream signal transduction pathways [7]. According to the protein-only hypothesis [1], the Scrapie isoform, acting as a seed, promotes the conversion of the unstructured N-terminal domain of the PrPC into a β-sheet rich structure (with the help of a supposed protein X). The exact mechanism of this conformational change or prion conversion is unclear but may involve the initial formation of dimers

Methods

Results

Conclusion