1Mol. Psychiatry 2016 Feb 21: 205-15
TitleGlobal quantitative analysis of phosphorylation underlying phencyclidine signaling and sensorimotor gating in the prefrontal cortex.
AbstractPrepulse inhibition (PPI) is an example of sensorimotor gating and deficits in PPI have been demonstrated in schizophrenia patients. Phencyclidine (PCP) suppression of PPI in animals has been studied to elucidate the pathological elements of schizophrenia. However, the molecular mechanisms underlying PCP treatment or PPI in the brain are still poorly understood. In this study, quantitative phosphoproteomic analysis was performed on the prefrontal cortex from rats that were subjected to PPI after being systemically injected with PCP or saline. PCP downregulated phosphorylation events were significantly enriched in proteins associated with long-term potentiation (LTP). Importantly, this data set identifies functionally novel phosphorylation sites on known LTP-associated signaling molecules. In addition, mutagenesis of a significantly altered phosphorylation site on xCT (SLC7A11), the light chain of system xc-, the cystine/glutamate antiporter, suggests that PCP also regulates the activity of this protein. Finally, new insights were also derived on PPI signaling independent of PCP treatment. This is the first quantitative phosphorylation proteomic analysis providing new molecular insights into sensorimotor gating.
SCZ Keywordsschizophrenia
2J Psychiatr Res 2016 Jan 72: 58-63
TitleDecreased mRNA expression for the two subunits of system xc(-), SLC3A2 and SLC7A11, in WBC in patients with schizophrenia: Evidence in support of the hypo-glutamatergic hypothesis of schizophrenia.
AbstractThe cystine/glutamate antiporter system xc(-), playing a critical role in the regulation of glutamate release, might be implicated in the pathogenesis of schizophrenia. This study examined whether peripheral expressions of the system xc(-) subunits are characteristic of schizophrenia.
Expression of system xc(-) genes including SLC3A2 and SLC7A11 in peripheral WBCs of patients with schizophrenia and healthy individuals were measured using quantitative PCR. Both psychotropic-free and medicated patients with schizophrenia were recruited.
A total of 96 schizophrenia patients (48 medicated and 48 drug-free) and 96 healthy individuals were enrolled. The mRNA expression levels using the 2(-??C)T Method of both SLC3A2 and SLC7A11 in WBCs of schizophrenia patients were markedly lower than that of healthy individuals (0.22 and 0.48, respectively, the mRNA expression level of normal controls was normalized to 1). There was no significant difference between medicated and drug-free patients in the mRNA expressions of both SLC3A2 and SLC7A11. The Receiver Operating Characteristics (ROC) analysis of SLC3A2 mRNA levels using ??CT values for drug-free schizophrenia patients vs. healthy controls determined an optimal cutoff value, 0.801, with high sensitivity (1.000) and modest specificity (0.694) (area under curve of ROC = 0.794).
This is the first study indicating that the peripheral mRNA expression levels of SLC7A11 and SLC3A2 may be lower in patients with schizophrenia than healthy individuals. The finding supports the hypo-glutamatergic neurotransmission hypothesis in schizophrenia. Whether mRNA expression of system xc(-) subunits genes, particularly SLC3A2, could serve as a potential biomarker of schizophrenia needs further studies.
SCZ Keywordsschizophrenia