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CASPR2 Autoimmune Antibodies Induce Neuronal Hyperactivity in Human Brain Organoids

Ana Rafaela Oliveira1,2,3, Giuseppe Cammarata1,4, Catarina Seabra1,3

  • 1CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Journal of Neurochemistry
|February 23, 2026
PubMed

Insights

Maternal autoantibodies targeting Contactin-associated protein-like 2 (CASPR2) may disrupt fetal brain development. Exposure to anti-CASPR2 antibodies in human neural organoids induced neuronal hyperexcitability, a hallmark of neurodevelopmental disorders.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Immunology

Background:

  • Gestational transfer of brain-reactive antibodies poses risks for neurodevelopmental disorders.
  • Contactin-associated protein-like 2 (CASPR2) is a target for maternal autoantibodies implicated in fetal neurodevelopment.
  • The precise impact of CASPR2 antibodies on human brain development is not well understood.

Purpose of the Study:

  • To investigate the neurophysiological effects of CASPR2 autoantibodies on human brain development.
  • To elucidate the mechanisms underlying CASPR2 antibody-induced neurodevelopmental alterations.

Main Methods:

  • Cultured unguided human neural organoids for 6 months in media with anti-CASPR2 antibodies.
  • Performed neurophysiological characterization using whole-cell patch-clamp and calcium imaging in acute organoid slices.

Main Results:

  • CASPR2 antibody exposure significantly increased spontaneous synaptic activity.
  • Enhanced maximal frequency of action potential firing and spontaneous network activity were observed.
  • Alterations in action potential waveform suggest CASPR2's role in regulating voltage-gated potassium channels.

Conclusions:

  • CASPR2 autoantibodies induce neuronal hyperexcitability in human neural organoids.
  • This hyperexcitability phenotype mirrors findings in neurodevelopmental disorder models.
  • CASPR2 autoantibodies may play a pathological role in driving neuronal hyperexcitability during development.
Keywords:
CASPR2autismbrain organoidselectrophysiologyhyperexcitabilitymaternal autoantibodiesneurodevelopment

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