A double hit affecting the IKZF1-IKZF2 tandem in immune cells of schizophrenic patients regulate specific symptoms

A double hit affecting the IKZF1-IKZF2 tandem in immune cells of schizophrenic patients regulate specific symptoms Abstract Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients’ peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive-negative-cognitive) of schizophrenic-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from human patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenic-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia. Competing Interest Statement The authors have declared no competing interest. Subject Area - Biochemistry (17728) - Bioengineering (13916) - Bioinformatics (42037) - Biophysics (21488) - Cancer Biology (18636) - Cell Biology (25552) - Clinical Trials (138) - Developmental Biology (13401) - Ecology (19940) - Epidemiology (2067) - Evolutionary Biology (24367) - Genetics (15621) - Genomics (22545) - Immunology (17764) - Microbiology (40475) - Molecular Biology (17208) - Neuroscience (88744) - Paleontology (667) - Pathology (2842) - Pharmacology and Toxicology (4834) - Physiology (7659) - Plant Biology (15175) - Synthetic Biology (4304) - Systems Biology (9834) - Zoology (2272)