Hippocampal proteomic and metabonomic abnormalities in neurotransmission and oxidative stress pathways in a chronic phencyclidine rat model

Schizophrenia is a neuropsychiatric disorder affecting 1% of the world’s population. Due to a broad range of symptoms and wide heterogeneity, current therapeutic approaches in schizophrenia fail to treat all symptomatic manifestations of the disease. Therefore, new models that reproduce core pathological features of schizophrenia are needed for the elucidation of unidentified pathological disease mechanisms. Here, we employ a comprehensive global label-free liquid chromatographymass spectrometry (LC-MS) proteomic and metabonomic profiling analysis combined with targeted proteomics (selected reaction monitoring and multiplex-immunoassay) of serum and brain tissues from a chronic phencyclidine (PCP) rat model, in which NMDA-receptor hypofunction is induced through non-competitive N-methyl-D-aspartate (NMDA) antagonism. Using multiplex immunoassay, we identified serum abnormalities in cytokines (IL-5, IL-2, IL-1β) and the fibroblast-growth factor-2 levels, as peripheral biomarkers of PCP treatment. In order to find potential novel drug targets and to elucidate the pathways associated with the disease, extensive proteomic and metabonomic brain tissue profiling was employed. This revealed a more prominent effect of chronic PCP treatment on the hippocampal proteome and metabonome compared to the frontal cortex. Bioinformatic pathway analysis confirmed the abnormalities in NMDA-receptor associated pathways in both brain regions, as well as alterations in other neurotransmitter systems such as kainate, AMPA and GABAergic signalling in the hippocampus. Metabonomic profiling revealed changes in phosphoand glycolipids, which was further supported by findings of oxidative stress (superoxide dismutase) on the protein level. These molecular changes parallel findings observed in human schizophrenia. The present study could lead to increased understanding of how perturbed glutamate receptor signalling affects other relevant biological pathways in schizophrenia and therefore support drug discovery efforts for improved treatment of patients suffering from this debilitating psychiatric disorder.