NMDA receptor antagonism by phencyclidine reduces NWASP and WAVE1 protein expression and reduces levels of myelination markers in the prefrontal cortex of rats

N-methyl-D-aspartate (NMDA) receptor antagonism by perinatal phencyclidine (PCP) treatment leads to neuronal damage and causes long-term behavioural alterations in rodents. It is routinely used to model pathological processes in the brain that may be present in schizophrenia, such as alterations to dendritic development, and disruptions to myelin processes. Both of these processes occur during brain development and are highly implicated in the schizophrenia pathophysiology. Changes to the polymerization and reorganization of the actin cytoskeleton can have significant effects on the morphology and dynamics of the dendrites within the brain. Actin regulation is primarily regulated by neural Wiskott-Aldrich syndrome protein (NWASP), and WASP-family verprolin homology protein-1 (WAVE1). Here we have examined the role of actin related, cytoskeletal proteins NWASP and WAVE1 in a neurodevelopmental model of schizophrenia using PCP to determine if these signaling pathways are altered in the prefrontal cortex and hippocampus throughout different stages of neurodevelopment. Male Sprague Dawley rats were injected subcutaneously with PCP (10 mg/kg) or saline at postnatal days (PN) 7, 9 and 11. Rats (n=6/group) were sacrificed at PN 12, 5 weeks or 14 weeks. Relative expression levels of protein expression were examined in the prefrontal cortex and hippocampus of the treated rats. NWASP, WAVE1 and MBP were decreased (0.001≤p≤0.032) in the prefrontal cortex of PCP treated rats at PN12. At 5 weeks of age, NWASP was reduced in the prefrontal cortex (p=0.037) and WAVE1 was reduced in the hippocampus (p=0.006). At 14 weeks, there were no significant changes in any of the tested proteins (p > 0.05). This is the first report of an alteration in NWASP and WAVE1 proteins in the rat brain, directly following NMDA receptor antagonism by PCP treatment in early development. These findings suggest that alterations in these important scaffolding related proteins may contribute to the development of deficits in myelination and cognitive performance in the brain.

© All rights are reserved by Fernandez-Enright et al. Published with a Creative Commons Attribution License (CC BY) by Journal of Pharmaceutics & Pharmacology.