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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.

Original publication

DOI

10.1007/s00401-017-1751-5

Type

Journal article

Journal

Acta Neuropathol

Publication Date

10/2017

Volume

134

Pages

567 - 583

Keywords

Autism, CASPR2, Intellectual development, Maternal antibodies, Maternal-to-fetal mouse model, Neurodevelopmental disorders, Animals, Animals, Outbred Strains, Autoantibodies, Brain, Encephalitis, Female, Glutamic Acid, HEK293 Cells, Humans, Immunoglobulin G, Male, Membrane Proteins, Mice, Knockout, Microglia, Nerve Tissue Proteins, Neurons, Prefrontal Cortex, Pregnancy, Prenatal Exposure Delayed Effects, Proteins, Random Allocation, Social Behavior