Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model

Schizophrenia is a neuropsychiatric
disorder affecting 1% of the
world’s population. Due to both a broad range of symptoms and
disease heterogeneity, current therapeutic approaches to treat schizophrenia
fail to address all symptomatic manifestations of the disease. Therefore,
disease models that reproduce core pathological features of schizophrenia
are needed for the elucidation of pathological disease mechanisms.
Here, we employ a comprehensive global label-free liquid chromatography–mass
spectrometry proteomic (LC–MSE) and metabonomic
(LC–MS) profiling analysis combined with the targeted proteomics
(selected reaction monitoring and multiplex immunoassay) of serum
and brain tissues to investigate a chronic phencyclidine (PCP) rat
model in which glutamatergic hypofunction is induced through noncompetitive
NMDAR-receptor antagonism. Using a multiplex immunoassay, we identified
alterations in the levels of several cytokines (IL-5, IL-2, and IL-1β)
and fibroblast growth factor-2. Extensive proteomic and metabonomic
brain tissue profiling revealed a more prominent effect of chronic
PCP treatment on both the hippocampal proteome and metabonome compared
to the effect on the frontal cortex. Bioinformatic pathway analysis
confirmed prominent abnormalities in NMDA-receptor-associated pathways
in both brain regions, as well as alterations in other neurotransmitter
systems such as kainate, AMPA, and GABAergic signaling in the hippocampus
and in proteins associated with neurodegeneration. We further identified
abundance changes in the level of the superoxide dismutase enzyme
(SODC) in both the frontal cortex and hippocampus, which indicates
alterations in oxidative stress and substantiates the apoptotic pathway
alterations. The present study could lead to an increased understanding
of how perturbed glutamate receptor signaling affects other relevant
biological pathways in schizophrenia and, therefore, support drug
discovery efforts for the improved treatment of patients suffering
from this debilitating psychiatric disorder.