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%; pb0.05); increased erbB4 and p-erbB4 (+18–27%; pb0.01) at 5 weeks;
and decreased erbB4 and p-erbB4 (−16–18%; pb0.05) along with increased Nrg1 (+33%; pb0.01)
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%; pb0.001); however NMDA receptor subunits
and PSD-95 showed increases at PN12 and 5 weeks (+20–32%; pb0.05), and decreases at
20 weeks (−22–29%; pb0.05). 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.
© 2011 Elsevier B.V. and ECNP. All rights reserved.