Abstract
The aberrant formation and function of neuronal synapses are recognized as major phenotypes in many cases of neurodevelopmental (NDDs) and -psychiatric disorders (NPDs). A growing body of research has identified an expanding number of susceptibility genes encoding proteins with synaptic function. Here, we present the first brain-focused characterization of a potential new susceptibility gene, ARHAGP8, which encodes a Rho GTPase activating protein (RhoGAP). Accumulating evidence suggests that ARHGAP8 plays a pivotal role in the pathogenesis of NPDs/NDDs. We provide the first evidence for ARHGAP8 as a novel player at excitatory synapses, with its synaptic localisation linked to the presence of the developmentally important NMDA receptor subunit GluN2B. By increasing ARHGAP8 levels in hippocampal neurons to mimic elevated levels found in subsets of patients, we observed reductions in dendritic complexity and spine volume, accompanied by a significant decrease in synaptic AMPA receptor-mediated transmission. These results suggest that ARHGAP8 plays a role in shaping the morphology and function of excitatory synapses, and prompt further investigation of ARHGAP8 as a candidate gene in NDDs/NPDs.
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Numerical data set is made available on Zenodo92.
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Acknowledgements
We would like to acknowledge Professor Boon Chuan Low of the Cell Signalling and Developmental Biology Group, Mechanobiology Institute of National University of Singapore, for the kind gift of the GFP-BPGAP1 and HA-BPGAP1 plasmids (including the mutants). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), and FCT, I.P under the project code LCF/PR/HP20/52300003. The work was also funded by the European Regional Development Fund (ERDF), through the COMPETE 2020 — Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT, under projects UIDB/04539/2020, UIDP/04539/2020, LA/P/0058/2020, SFRH/BD/51960/2012, PTDC/BIA-CEL/2286/2020, Marie Skłodowska-Curie Action Individual Fellowship 101031398, IBRO Return Home Fellowship 2021, 2020.01761. CEECIND/CP1609/CT0003, 2022.05386.PTDC and European Union Horizon 2020 Research and Innovation programme under grant agreement 857524.
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J.S., Â.S.I., J.F., D.S., R.S., N.B., L.F.R., P.P., J.B.R., A.L.C. – research design; J.S., Â.S.I., J.F., D.S., R.S., N.B. performance of experiments and analysis; Manuscript written by J.S., J.F. and A.L.C. with contributions made by all authors.
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Schmidt, J., Inácio, Â.S., Ferreira, J. et al. Neuronal ARHGAP8 controls synapse structure and AMPA receptor-mediated synaptic transmission. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09884-5
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DOI: https://doi.org/10.1038/s42003-026-09884-5
