Perturbation of Cell-subtype specific Active Kinome Networks in Schizophrenia

Schizophrenia is a serious illness with significant effects on patients and their families. Because the disease impacts executive function, the Dorsolateral Prefrontal Cortex (DLPFC) has been a focus of study. We previously reported altered protein kinase activity, including AKT, in postmortem brain samples from patients with schizophrenia. Now, we extend this research to the cellular level, concentrating on frontal cortical pyramidal neurons. Using laser capture microdissection, we isolated DLPFC pyramidal neurons from matched pairs of schizophrenia and control postmortem brain samples (n = 20 per group). We then used the PamChip STK kinome array assay for high-throughput analysis of kinase activity. With well-established bioinformatics methods, we identified upstream kinases involved in schizophrenia. Several kinases of interest emerged, such as c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (ERK), and p38 mitogen-activated protein kinases (P38). Of these, the P38 kinases were of particular importance as they are involved in the inflammation cascade and immune function. Next, we applied a new technique to identify kinase interaction networks within high-throughput kinase activity data. This modeling enabled us to detect network-level changes in pyramidal neurons in schizophrenia. This is the first study to analyze the subkinome at the cellular level in schizophrenia and to reveal active kinome network changes in this often-devastating illness. Prevailing hypotheses regarding the etiology of schizophrenia include aberrant synapse turnover, which is mediated by microglia and immune function pathways. Our findings offer a crucial new starting point for understanding how disrupted signaling networks may mediate the pathophysiology of this often devastating severe mental illness.