Perinatal phencyclidine treatment alters neuregulin 1/erbB4 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 (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.