Disrupted Brain Organoid Circuitry, Structural Organization, and Spine Morphology in 7q11.23 Copy Number Variant Syndromes

Hwang, I.; Yeo, J. S.; Almeida, M. C.; Cupajita, B. M.; Carrettiero, D. C.; Acosta-Uribe, J.; Han, A.; Ngo, A.; Camargo, C.; Budisteanu, M.; Arghir, A.; Osborne, L. R.; Ellis, J.; Smith, I. T.; Goard, M. J.; Kosik, K. S.

doi:10.64898/2026.08.11.744287

bioRxiv · 10.64898/2026.08.11.744287

Disrupted Brain Organoid Circuitry, Structural Organization, and Spine Morphology in 7q11.23 Copy Number Variant Syndromes

Hwang, I.·Yeo, J. S.·Almeida, M. C.·Cupajita, B. M.·Carrettiero, D. C.·Acosta-Uribe, J.·Han, A.·Ngo, A.·Camargo, C.·Budisteanu, M.·Arghir, A.·Osborne, L. R.·Ellis, J.·Smith, I. T.·Goard, M. J.·Kosik, K. S.

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Abstract

The 7q11.23 chromosomal region represents a model of gene dosage-dependence, where a hemizygous deletion causes Williams Syndrome (WS) and a duplication leads to 7q11.23 Duplication Syndrome (Dup7). It is not understood how these copy number variations (CNVs) disrupt development and functional cortical circuit assembly. Utilizing iPSC-derived cerebral organoids and longitudinal imaging from post-differentiation day 30 to 150, we characterized the aberrant neural rosette morphogenesis in WS and Dup7 during early stages, establishing an early structural divergence from control lines. We observed accelerated early cortical rosette morphogenesis in WS, characterized by a premature increase in both rosette number and layer thickness compared to controls. In contrast, Dup7 organoids consistently exhibit a significantly lower number and reduced thickness of rosettes from early stages onward. This early structural disruption progressively impacted synaptic-level architecture as the organoids matured. Dendritic spine characterization at later stages revealed Dup7 organoids exhibited a significantly higher dendritic spine density compared to WS. Pharmacological antagonism of CCR5 (C-C chemokine receptor type 5) with Maraviroc significantly enhanced dendritic spine density in control and WS organoids; however, this effect was absent in Dup7. To determine how these structural anomalies translate into circuit-level behavior, we performed longitudinal calcium imaging using GCaMP. Control organoids sustained synchronized activity and high spike correlations at all time points. This synchronization was delayed and highly transient in WS organoids, and completely abolished in Dup7 organoids, which exhibit significantly low spike correlations at all stages. Developmentally, GABA changes from acting as an excitatory signal in the immature brain to an inhibitory signal as the brain matures. As control lines matured gabazine-induced desynchronization progressively diminished, but persisted in WS organoids. Dup7 organoids failed to establish synchronization at any developmental time point, but displayed a negligible increased synchrony following gabazine treatment. These functional aberrations were paralleled by genotype-specific defects in structural organization, specifically in rosette morphogenesis and dendritic spine density. Collectively, our findings demonstrate that 7q11.23 CNVs trigger pathogenic neurodevelopmental defects by derailing the trajectories of structural organization, circuit assembly, and functional synchronization during cortical maturation.

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Hwang, I., Yeo, J. S., Almeida, M. C., Cupajita, B. M., Carrettiero, D. C., Acosta-Uribe, J., Han, A., Ngo, A., Camargo, C., Budisteanu, M., Arghir, A., Osborne, L. R., Ellis, J., Smith, I. T., Goard, M. J., Kosik, K. S.. 2026-08-20. Disrupted Brain Organoid Circuitry, Structural Organization, and Spine Morphology in 7q11.23 Copy Number Variant Syndromes. https://doi.org/10.64898/2026.08.11.744287

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