Clozapine combined with rTMS downregulating EGR3 improves cognitive impairment in a mouse model of schizophrenia

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Despite its status as a crucial symptom of schizophrenia, the underlying mechanisms of cognitive dysfunction remain inscrutable, and the quest for a definitive treatment continues to be elusive.Our comprehensive research has uncovered significantly elevated expression levels of EGR3 in the serum of schizophrenia patients, as well as in the prefrontal cortex of MK-801-induced schizophrenia-like model mouse.the objective of this study was to delve into the role of EGR3 in alleviating cognitive impairment in schizophrenia through the combined treatment of clozapine and rTMS. We aspire to uncover the potential mechanisms underlying this combined therapy's effect on cognitive impairment in schizophrenia by exploring the expression and functional alterations of EGR3 in depth. Notably, these elevated levels were found to correlate with varying degrees of cognitive impairment, providing valuable insights into the complex mechanisms underlying schizophrenia. Clozapine combined with rTMS was used to evaluate the cognitive function of patients during treatment, and Enzyme-linked immunosorbent Assay was used to detect the expression of EGR3 to explore its efficacy and study the correlation between EGR3 and cognitive function. Schizophrenia model mice were induced with didrozepine maleate (MK-801), treated with clozapine rTMS, and one group treated with EGR3 agonist. Male BALB/C mice were randomly divided into control group, schizophrenia group, clozapine treatment group and clozapine combined with repeated TMS treatment group. Water maze behavior experiment was performed. Then, the prefrontal cortex tissues of the mice were taken for protein western blot detection and immunohistochemical detection to detect the expression of EGR3 in the prefrontal cortex. To explore the effect of clozapine combined with rTMS on the expression of EGR3, Bcl-2 and Caspase-3. The expression of EGR3 gene, Bcl-2 protein and Caspase-3 egg white in prefrontal cortex of mice were detected by Western blot. The expression of Bcl-2 egg white and Caspase-3 protein in the skin of the anterior frontal lobe of rats was measured by immunohistochemistry. Remarkably, the synergistic combination of clozapine and repetitive transcranial magnetic stimulation (rTMS) exhibited profound effects in our model mice. Not only did it effectively lower EGR3 levels in the prefrontal cortex, but it also modulated the expression of Bcl-2 and Caspase-3, ultimately leading to significant improvements in cognitive function. These groundbreaking findings highlight the immense potential of the clozapine-rTMS combination in alleviating cognitive impairment in MK-801-induced schizophrenia-like model mouse, thus providing invaluable insights into innovative therapeutic strategies to address cognitive deficits associated with schizophrenia.

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