Schizophrenia (SCZ) is a debilitating, destructive, and chronic mental disorder and affects approximately one percent of the human population. Diagnosis in psychiatry is based on the patient\'s descriptions of his/her symptoms, interviewer\'s observations, history of disorder over time, and response to treatment. All of these data measure phenotype-based functions. But it appears that accurate diagnosis of such a complex disorder must be based on valid and reliable factors. In the present study, gene selection was based on the possible role of γ-aminobutyric acid (GABA) in psychopathology of SCZ and expression in blood. We evaluated the association of Na+-K+-Cl- co-transporter 1 (NKCC1) and K+-Cl- co-transporter 2 (KCC2) genes\' messenger ribonucleic acid (mRNA) levels, and also the NKCC1/KCC2 ratio with positive and negative syndrome scale (PANSS) and brief psychiatric rating scale (BPRS) scores in an SCZ group. By using real-time PCR (RT-PCR), the present study is the first attempt to explore levels of NKCC1 and KCC2 expression at mRNA level and their relative expression in human peripheral blood of patients with SCZ. Our results showed that the NKCC1 to KCC2 mRNA ratio is significantly increased (but based on the delta cycle of threshold [∆Ct] is significantly lower) in the total sample of cases rather than controls (p = 0.045) and also higher in male sample cases rather than male controls (p = 0.016). In female samples, we found a trend toward a significant effect between the case and control participants (p = 0.075). We also found statistically significant association between mRNA of NKCC1 and KCC2 genes and NKCC1/KCC2 mRNA ratio with the positive and negative syndrome scale (PANSS) and brief psychiatric rating scale (BPRS) scores.

Schizophrenia is a major psychiatric disorder, but the molecular mechanisms leading to its initiation or progression remain unclear. To elucidate the pathophysiology of schizophrenia, we used an in vitro neuronal cell culture model involving human induced pluripotent stem cells (hiPSCs) derived from a monozygotic-twin discordant schizophrenia pair. The cultured neurons differentiated from hiPSCs were composed of a mixture of glutamatergic excitatory neurons and gamma aminobutyric acid (GABA)ergic inhibitory neurons. In the electrophysiological analysis, a different pattern of spontaneous neuronal activity was observed under the condition without any stimulants. The frequency of spontaneous excitatory post-synaptic currents (sEPSCs) was significantly higher in the hiPSC-derived neurons of the patient with schizophrenia than in the control sibling at day-in-vitro 30. However, the synaptic formation was not different between the patient with schizophrenia and the control sibling during the same culture period. To explain underlying mechanisms of higher excitability of presynaptic cells, we focused on the potassium-chloride co-transporter KCC2, which contributes to excitatory-to-inhibitory GABA polarity switch in developing neurons. We also revealed the altered expression pattern of KCC2 in hiPSC-derived neurons from the patient with schizophrenia, which could contribute to understanding the pathology of schizophrenia in the developing nervous system.