👤 Natalie Matosin

Postnatal administration of phencyclidine (PCP) in rodents causes major brain dysfunction leading to severe disturbances in behavior lasting into adulthood. This model is routinely employed to model psychiatric disorders such as schizophrenia, as it reflects schizophrenia-related brain disturbances including increased apoptosis, and disruptions to myelin and plasticity processes. Leucine-rich repeat and Immunoglobin-like domain-containing protein 1 (Lingo-1) is a potent negative regulator of both axonal myelination and neurite extension. The Nogo receptor (NgR)/tumor necrosis factor (TNF) receptor orphan Y (TROY) and/or p75 neurotrophin receptor (p75) complex, with no lysine (K) (WNK1) and myelin transcription factor 1 (Myt1) are co-receptors or cofactors in Lingo-1 signaling pathways in the brain. We have examined the developmental trajectory of these proteins in a neurodevelopmental model of schizophrenia using PCP to determine if Lingo-1 pathways are altered in the prefrontal cortex throughout different stages of life. Sprague-Dawley rats were injected with PCP (10 mg/kg) or saline on postnatal days (PN)7, 9, and 11 and killed at PN12, 5 or 14 weeks for measurement of Lingo-1 signaling proteins in the prefrontal cortex. Myt1 was decreased by PCP at PN12 ( Show less

Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippocampal deficits seen in schizophrenia. Show less