Perinatal administration of phencyclidine alters expression of Lingo-1 signaling pathway proteins in the prefrontal cortex of juvenile and adult rats.

Jessica L Andrews,Xu-Feng Huang,Natalie Matosin,Kelly A Newell,Francesca Fernandez

doi:10.1042/ns20180059

Abstract

Postnatal administration of phencyclidine (PCP) in rodents causes major brain dysfunction leading to severe disturbances in behavior lasting into adulthood. This model is routinely employed to model psychiatric disorders such as schizophrenia, as it reflects schizophrenia-related brain disturbances including increased apoptosis, and disruptions to myelin and plasticity processes. Leucine-rich repeat and Immunoglobin-like domain-containing protein 1 (Lingo-1) is a potent negative regulator of both axonal myelination and neurite extension. The Nogo receptor (NgR)/tumor necrosis factor (TNF) receptor orphan Y (TROY) and/or p75 neurotrophin receptor (p75) complex, with no lysine (K) (WNK1) and myelin transcription factor 1 (Myt1) are co-receptors or cofactors in Lingo-1 signaling pathways in the brain. We have examined the developmental trajectory of these proteins in a neurodevelopmental model of schizophrenia using PCP to determine if Lingo-1 pathways are altered in the prefrontal cortex throughout different stages of life. Sprague–Dawley rats were injected with PCP (10 mg/kg) or saline on postnatal days (PN)7, 9, and 11 and killed at PN12, 5 or 14 weeks for measurement of Lingo-1 signaling proteins in the prefrontal cortex. Myt1 was decreased by PCP at PN12 (P=0.045), and at 14 weeks PCP increased Lingo-1 (P=0.037), TROY (P=0.017), and WNK1 (P=0.003) expression. This is the first study reporting an alteration in Lingo-1 signaling proteins in the rat prefrontal cortex both directly after PCP treatment in early development and in adulthood. We propose that Lingo-1 pathways may be negatively regulating myelination and neurite outgrowth following the administration of PCP, and that this may have implications for the cortical dysfunction observed in schizophrenia.

Highlights

Phencyclidine, known as PCP, is primarily a potent non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, but is an agonist for the dopamine D2 receptors [1,2,3] and to a lesser extent binds opiate, nicotinic, and muscarinic cholinergic receptors [4,5,6,7]
Bearing in mind the role of Lingo-1 signaling proteins in myelin related processes, and the fact that we found Lingo-1 protein expression to be significantly upregulated in the human dorsolateral prefrontal cortex (DLPFC) in schizophrenia [31], the present study focuses on Lingo-1 signaling protein alterations in the prefrontal cortex of the rats in our model
Levels of Lingo-1, and signaling partners TNF receptor orphan Y (TROY), WNK1 and Myelin transcription factor-1 (Myt1) protein expression are altered in the prefrontal cortex of rats throughout development by perinatal administration of PCP

Summary

Introduction

Phencyclidine, known as PCP, is primarily a potent non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, but is an agonist for the dopamine D2 receptors [1,2,3] and to a lesser extent binds opiate, nicotinic, and muscarinic cholinergic receptors [4,5,6,7]. Since the PCP-induced behaviors in rodents are translatable to the psychomimetic effects in both humans and other higher order primates, the administration of PCP is one of the best known pharmacological models of schizophrenia [10,11,12]. Similar to neurons, oligodendrocytes are extremely sensitive to the effects of PCP during development [17], and myelination has been shown to be significantly affected by PCP treatment both in utero and postnatally [16,17]. We have previously shown in this rat model that myelin basic protein (MBP), a marker of mature oligodendrocytes and myelination, is significantly reduced in early development by perinatal administration of PCP [20]. Considering the significant role of oligodendrocytes in axonal connectivity, conduction and myelination, disruption to these critical processes during early neurodevelopment can have significant negative consequences, impacting on normal brain development

Results

Discussion

Conclusion