Perinatal phencyclidine treatment alters neuregulin 1erbB4 expression and activation in later life.
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 (n5group) were treated with PCP (10 mgkg) 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 receptorNrg1 signaling in the prefrontal cortex and hippocampus. In the cortex, PCP treatment altered Nrg1erbB4 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 Nrg1erbB4 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 Nrg1erbB4 expression which could be important in understanding pathological processes which might be involved in schizophrenia.