Synaptic microRNA dysregulation orchestrates aberrant glutamatergic transmission in a human neuronal model of 22q11.2 deletion syndrome
- 1Emory University
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.
Related
- Serotonergic regulation of neuronal excitability and glutamatergic synaptic transmission in rat claustrum
- TREM2 Orchestrates Myeloid Cell Programming and Immune Dysregulation in Pulmonary Hypertension
- Sequential maturation of supramammillary glutamatergic/GABAergic co-transmission onto adult-born dentate granule cells
- Dysregulation of cAMP-PKA-mediated mechanisms disrupts basal synaptic function in the absence of presynaptic FMRP
- MicroRNA dysregulation in pemphigus: a systematic review of expression profiles and molecular targets
BibTeX
@misc{niu2026synaptic,
title = {{Synaptic microRNA dysregulation orchestrates aberrant glutamatergic transmission in a human neuronal model of 22q11.2 deletion syndrome}},
author = {W. Niu and J. Guo and X. Ran and D. Parker and X. Li and S. Yu and S. Imes and R. Purcell and C. Michalski and E. Guo and S. Y. Jiang and E. Xu and G. J. Bassell and J. G. Mulle and O. Y. Ousley and B. Pearce and Y. Feng and C. E. Bearden and E. F. Walker and J. F. Cubells and Z. Qin and E. Duncan and Z. Wen},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.758925},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.758925v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Synaptic microRNA dysregulation orchestrates aberrant glutamatergic transmission in a human neuronal model of 22q11.2 deletion syndrome
AU - W. Niu
AU - J. Guo
AU - X. Ran
AU - D. Parker
AU - X. Li
AU - S. Yu
AU - S. Imes
AU - R. Purcell
AU - C. Michalski
AU - E. Guo
AU - S. Y. Jiang
AU - E. Xu
AU - G. J. Bassell
AU - J. G. Mulle
AU - O. Y. Ousley
AU - B. Pearce
AU - Y. Feng
AU - C. E. Bearden
AU - E. F. Walker
AU - J. F. Cubells
AU - Z. Qin
AU - E. Duncan
AU - Z. Wen
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.758925
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.758925v1
AB - 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.
ER -