title: Perinatal phencyclidine treatment alters neuregulin 1/erbB4 expression and activation in later life.
abstract: Schizophrenia is a complex and devastating mental disorder of unknown etiology. Hypofunction of N-methyl-D-aspartate (NMDA) receptors are implicated in the disorder, since phencyclidine (PCP) and other NMDA receptor antagonists mimic schizophrenia-like symptoms in humans and animals so well. Moreover, genetic linkage and post mortem studies strongly suggest a role for altered neuregulin 1 (Nrg1)/erbB4 signaling in schizophrenia pathology. This study investigated the relationship between the NMDA receptor and Nrg1 signaling pathways using the perinatal PCP animal model. Rats (n=5/group) were treated with PCP (10 mg/kg) or saline on postnatal days (PN) 7, 9 and 11 and were sacrificed on PN12, 5 weeks and 20 weeks for biochemical analyses. Western blotting was used to determine total and phosphorylated levels of proteins involved in NMDA receptor/Nrg1 signaling in the prefrontal cortex and hippocampus. In the cortex, PCP treatment altered Nrg1/erbB4 expression levels throughout development, including decreased Nrg1 and erbB4 at PN12 (-25-30%; p<0.05); increased erbB4 and p-erbB4 (+18-27%; p<0.01) at 5 weeks; and decreased erbB4 and p-erbB4 (-16-18%; p<0.05) along with increased Nrg1 (+33%; p<0.01) at 20 weeks. In the hippocampus, levels of Nrg1/erbB4 were largely unaffected apart from a significant decrease in p-erbB4 at 20 weeks (-13%; p<0.001); however NMDA receptor subunits and PSD-95 showed increases at PN12 and 5 weeks (+20-32%; p<0.05), and decreases at 20 weeks (-22-29%; p<0.05). This study shows that NMDA receptor antagonism early in development can have long term effects on Nrg1/erbB4 expression which could be important in understanding pathological processes which might be involved in schizophrenia.
authors.affiliation: Centre for Translational Neuroscience, School of Health Sciences, Illawarra Health and Medical Research Institute, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia. teresadb@uow.edu.au
authors.forename: Teresa Marie
authors.initials: TM
authors.lastname: du Bois
authors.forename: Kelly Anne
authors.initials: KA
authors.lastname: Newell
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D020890:Neuregulin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010622:Phencyclidine / Q000008:administration & dosage*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D020890:Neuregulin-1; C490580:Nrg1 protein, rat; D016194:Receptors, N-Methyl-D-Aspartate; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D010622:Phencyclidine