Mecp2 deficiency impairs microscale cortical network topology and dynamics in a Rett syndrome mouse model

Dunn, A. W. E.; Sit, T. P. H.; Feord, R. C.; Soltani, A.; Yuan, Y.; Turner, R.; Loureiro, I.; Eglen, S. J.; Paulsen, O.; Mierau, S. B.

doi:10.64898/2025.12.17.694950

bioRxiv · 10.64898/2025.12.17.694950

Mecp2 deficiency impairs microscale cortical network topology and dynamics in a Rett syndrome mouse model

Dunn, A. W. E.·Sit, T. P. H.·Feord, R. C.·Soltani, A.·Yuan, Y.·Turner, R.·Loureiro, I.·Eglen, S. J.·Paulsen, O.·Mierau, S. B.

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Abstract

Rett syndrome is a debilitating neurodevelopmental disorder with cerebral processing impairments caused by MECP2 loss-of-function mutations. Mecp2-deficient mouse models reveal disruptions of microscale cortical circuits. Yet how cellular-scale information processing is altered in Mecp2-deficient microscale functional networks is unknown. We investigated the development of functional connectivity, network topology, and dynamics in microelectrode array (MEA) recordings of primary cortical cultures from Mecp2-deficient and wild-type mice. Mecp2-deficient cortical networks developed more slowly and showed decreased functional connectivity compared to wild-type, leading to smaller network size, density, and strength of connectivity. Altered network topological features in Mecp2-deficient microscale circuits predicted decreased efficiency and information-sharing capacity. This reveals developmental deficits in microscale functional networks, which may in turn underlie the cortical decline and severe cognitive disability in Rett syndrome. These findings also offer circuit-level targets and an in-vitro approach for evaluating new therapeutic products for restoring microscale network function.

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Dunn, A. W. E., Sit, T. P. H., Feord, R. C., Soltani, A., Yuan, Y., Turner, R., Loureiro, I., Eglen, S. J., Paulsen, O., Mierau, S. B.. 2025-12-19. Mecp2 deficiency impairs microscale cortical network topology and dynamics in a Rett syndrome mouse model. https://doi.org/10.64898/2025.12.17.694950

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