Synaptic microRNA dysregulation orchestrates aberrant glutamatergic transmission in a human neuronal model of 22q11.2 deletion syndrome

Niu, W.; Guo, J.; Ran, X.; Parker, D.; Li, X.; Yu, S.; Imes, S.; Purcell, R.; Michalski, C.; Guo, E.; Jiang, S. Y.; Xu, E.; Bassell, G. J.; Mulle, J. G.; Ousley, O. Y.; Pearce, B.; Feng, Y.; Bearden, C. E.; Walker, E. F.; Cubells, J. F.; Qin, Z.; Duncan, E.; Wen, Z.

doi:10.64898/2026.10.13.758925

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bioRxiv · 10.64898/2026.10.13.758925

Synaptic microRNA dysregulation orchestrates aberrant glutamatergic transmission in a human neuronal model of 22q11.2 deletion syndrome

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Abstract

22q11.2 Deletion Syndrome (22q11DS), the most prevalent chromosomal microdeletion disorder in humans (incidence ~1 in 4,000 live births), arises from hemizygous deletions of a 1.5-3.0 Mb region on chromosome 22. Notably, 20-30% of individuals with 22q11DS develop schizophrenia (SCZ) by early adulthood, making 22q11DS one of the strongest genetic risk factors for SCZ. However, the mechanisms by which the 22q11.2 deletion perturbs neuronal function and drive psychotic manifestations in 22q11DS remain poorly defined. In this study, we generated human 2D cortical neurons and 3D cortical organoids from induced pluripotent stem cells (iPSCs) derived from clinically well-characterized individuals with 22q11DS. Cellular and electrophysiological analyses revealed that 22q11DS neurons exhibit hyperexcitability, reduced glutamatergic synaptic transmission, and impaired homeostatic synaptic plasticity, which are pathophysiological hallmarks that may be relevant to the clinical, cognitive, and psychophysiological profiles of patients. Transcriptomic profiling of neurons and synaptosomes from 22q11DS cortical organoids uncovered dysregulated immune pathways and synaptic gene networks. Integrative mRNA-microRNA network analysis identified synergistic downregulation of hsa-miR-185-5p and hsa-miR-128-3p at synapses, driving aberrant regulation of immune and synaptic transcripts. Experimental knockdown of these microRNAs in control neurons recapitulated the molecular and functional phenotypes of 22q11DS neurons, thereby establishing a mechanistic link to synaptic dysfunction and impaired plasticity. Collectively, these findings delineate a multimodal mechanistic framework that bridges genetic vulnerability, synaptic pathology, and psychosis penetrance in 22q11DS, positioning dysregulated synaptic microRNAs as nodal regulators of neurodevelopmental networks and potential therapeutic targets.

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Niu, W., Guo, J., Ran, X., Parker, D., Li, X., Yu, S., Imes, S., Purcell, R., Michalski, C., Guo, E., Jiang, S. Y., Xu, E., Bassell, G. J., Mulle, J. G., Ousley, O. Y., Pearce, B., Feng, Y., Bearden, C. E., Walker, E. F., Cubells, J. F., Qin, Z., Duncan, E., Wen, Z.. 2026-10-15. Synaptic microRNA dysregulation orchestrates aberrant glutamatergic transmission in a human neuronal model of 22q11.2 deletion syndrome. https://doi.org/10.64898/2026.10.13.758925

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