Persistent microglial activation and synaptic loss with behavioral abnormalities in mouse offspring exposed to CASPR2-antibodies in utero

• Published in: Acta neuropathologica 2017-10, Vol.134 (4), p.567-583
• Main Authors: Coutinho, Ester, Menassa, David A., Jacobson, Leslie, West, Steven J., Domingos, Joana, Moloney, Teresa C., Lang, Bethan, Harrison, Paul J., Bennett, David L. H., Bannerman, David, Vincent, Angela
• Format: Article
• Language: English
• Subjects: Animals; Animals, Outbred Strains; Antibodies; Autoantibodies - administration & dosage; Autoantibodies - immunology; Brain - immunology; Brain - pathology; Children; Encephalitis - immunology; Female; Fetuses; Gestation; Glutamatergic transmission; Glutamic Acid - metabolism; HEK293 Cells; Humans; Immunoglobulin G; Immunoglobulin G - administration & dosage; Immunoglobulin G - metabolism; Immunoglobulins; Intracellular Signaling Peptides and Proteins; Intrauterine exposure; Male; Medicine; Medicine & Public Health; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice, Knockout; Microglia; Microglia - immunology; Microglia - pathology; Motor task performance; Neonates; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - immunology; Neurodevelopmental disorders; Neurons; Neurons - immunology; Neurons - pathology; Neurosciences; Original Paper; Parenchyma; Pathology; Prefrontal cortex; Prefrontal Cortex - immunology; Prefrontal Cortex - pathology; Pregnancy; Prenatal Exposure Delayed Effects; Proteins; Proteins - immunology; Random Allocation; Social aspects; Social Behavior; Somatosensory cortex; Synapses
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-017-1751-5

Gestational transfer of maternal antibodies against fetal neuronal proteins may be relevant to some neurodevelopmental disorders, but until recently there were no proteins identified. We recently reported a fivefold increase in CASPR2-antibodies in mid-gestation sera from mothers of children with intellectual and motor disabilities. Here, we exposed mice in utero to purified IgG from patients with CASPR2-antibodies (CASPR2-IgGs) or from healthy controls (HC-IgGs). CASPR2-IgG but not HC-IgG bound to fetal brain parenchyma, from which CASPR2-antibodies could be eluted. CASPR2-IgG exposed neonates achieved milestones similarly to HC-IgG exposed controls but, when adult, the CASPR2-IgG exposed progeny showed marked social interaction deficits, abnormally located glutamatergic neurons in layers V–VI of the somatosensory cortex, a 16% increase in activated microglia, and a 15–52% decrease in glutamatergic synapses in layers of the prefrontal and somatosensory cortices. Thus, in utero exposure to CASPR2-antibodies led to permanent behavioral, cellular, and synaptic abnormalities. These findings support a pathogenic role for maternal antibodies in human neurodevelopmental conditions, and CASPR2 as a potential target.