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CASPR2 autoimmune antibodies induce neuronal hyperactivity in human brain organoids

2026-02-01Artigo de investigação Acesso aberto
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dc.contributor.authorCammarata, Giuseppe
dc.contributor.authorCardoso, Ana Luísa
dc.contributor.authorCardoso, Ana Maria
dc.contributor.authorCarvalho, Ana Luísa
dc.contributor.authorCoutinho, Ester
dc.contributor.authorFernandes, Dominique
dc.contributor.authorFerreira, Lino
dc.contributor.authorGuedes, Joana
dc.contributor.authorLeite, Maria Isabel
dc.contributor.authorOliveira, Ana Rafaela
dc.contributor.authorOliveira, Guiomar
dc.contributor.authorPeça, João
dc.contributor.authorSantos, Henrique J.
dc.contributor.authorSantos, João Miguel Marques
dc.contributor.authorSeabra, Catarina
dc.contributor.authorSequeira, Diana
dc.date.accessioned2026-03-11T09:12:47Z
dc.date.available2026-03-11T09:12:47Z
dc.date.issued2026-02-01
dc.description.abstractGestational transfer of brain-reactive antibodies is a risk factor for neurodevelopmental disorders. Contactin-associated protein-like 2 (CASPR2) is a known target for pathogenic maternal autoantibodies which have been proposed to interfere with fetal neurodevelopment. However, the impact of CASPR2 antibodies on human brain development remains largely unknown. Here, to better understand the neurophysiological changes that occur in the presence of these pathogenic autoantibodies, we cultured unguided human neural organoids for a period of 6-months in media containing anti-CASPR2 antibodies. We then performed neurophysiological characterization via whole-cell patch-clamp and calcium imaging in acute organoid slices. Our results reveal that CASPR2 antibody exposure increased spontaneous synaptic activity, enhanced the maximal frequency of action potential firing and of spontaneous network activity. These findings are consistent with a state of neuronal hyperexcitability, a phenotype which is observed in several models of neurodevelopmental disorders. Mechanistically, the alterations observed in action potential waveform are in accordance with a role for CASPR2 in the regulation of voltage-gated potassium channels and a pathological role for CASPR2 autoantibodies in driving neuronal hyperexcitability.eng
dc.identifier.citationOliveira, A. R., Cammarata, G., Seabra, C., & Cardoso, A. M. et al. (2026). CASPR2 autoimmune antibodies induce neuronal hyperactivity in human brain organoids. Journal of Neurochemistry, 170(2), Article e70388. https://doi.org/10.1111/jnc.70388
dc.identifier.doi10.1111/jnc.70388
dc.identifier.eid105030859935
dc.identifier.issn0022-3042
dc.identifier.otherf6a32a38-d3ef-4493-8719-89ac21bf793f
dc.identifier.pmid41725505
dc.identifier.urihttp://hdl.handle.net/10400.14/57311
dc.language.isoeng
dc.peerreviewedyes
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAutism
dc.subjectBrain organoids
dc.subjectCASPR2
dc.subjectElectrophysiology
dc.subjectHyperexcitability
dc.subjectMaternal autoantibodies
dc.subjectNeurodevelopment
dc.titleCASPR2 autoimmune antibodies induce neuronal hyperactivity in human brain organoidseng
dc.typeresearch article
dspace.entity.typePublication
oaire.citation.issue2
oaire.citation.titleJournal of Neurochemistry
oaire.citation.volume170
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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