biostudies-literatureOliveira ARFundação para a Ciência e a TecnologiaBial FoundationEuropean Union Horizon 2020European Regional Development Fund (ERDF)Programa Operacional Potencial Humanoe70388https://www.ebi.ac.uk/biostudies/studies/S-EPMC12926859biostudies-literatureUnknown170(2)Gestational 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 synapJournal of neurochemistryCASPR2 Autoimmune Antibodies Induce Neuronal Hyperactivity in Human Brain Organoids.PMC129268592022.02604.PTDC799164813986FCT/NEURON/0002/2021427/2024PTDC/MED-NEU/5993/2020PTDC/NEU-SCC/3247/2014SFRH/BPD/120611/2016PD/BD/139074/2018Cammarata GSantos JMMFerreira LSequeira DCoutinho ECarvalho ALFernandes DSeabra CGuedes JOliveira ARLeite MISantos HJCardoso AMPeca JOliveira GCardoso ALfalseCASPR2 Autoimmune Antibodies Induce Neuronal Hyperactivity in Human Brain Organoids.Gestational 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 synap2026-01-01T00:00:00Z2026 Feb2026-07-16T18:32:39.238Z2026-07-11T03:08:00.776ZS-EPMC129268594172550510.1111/jnc.70388