Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice

Abstract

Autism spectrum disorder (ASD) occurs in 1 in 68 births, preferentially affecting males. It encompasses a group of neurodevelopmental abnormalities characterized by impaired social interaction and communication, stereotypic behaviors and motor dysfunction. Although recent advances implicate maternal brain-reactive antibodies in a causative role in ASD, a definitive assessment of their pathogenic potential requires cloning of such antibodies. Here, we describe the isolation and characterization of monoclonal brain-reactive antibodies from blood of women with brain-reactive serology and a child with ASD. We further demonstrate that male but not female mice exposed in utero to the C6 monoclonal antibody, binding to contactin-associated protein-like 2 (Caspr2), display abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as impairments in sociability, flexible learning and repetitive behavior. Anti-Caspr2 antibodies are frequent in women with brain-reactive serology and a child with ASD. Together these studies provide a methodology for obtaining monclonal brain-reactive antibodies from blood B cells, demonstrate that ASD can result from in utero exposure to maternal brain-reactive antibodies of single specificity and point toward the exciting possibility of prognostic and protective strategies.

Human gestational N‐methyl‐d‐aspartate receptor autoantibodies impair neonatal murine brain function

“…Binding to NMDAR might further retain and increase the ABs in the fetal brain, as in an injection model using animals with disrupted BBB. 9 Similarly, Caspr2 AB-containing maternal IgG fractions led to marked social interaction deficits in the offspring, disturbances in layer formation in somatosensory cortex, and increased microglial activation. In asymptomatic human mothers with low or even subthreshold serum NR1 AB titers, fetal NR1 IgG might still accumulate to a degree sufficient for permanent damage to the developing brain.…”

“…Similar to human placental FcRn, IgG is actively transported into the fetal murine circulation via the FcRn in the yolk sac. [6][7][8][9] Gestational transfer of IgG from mothers of children with ASD into mice resulted in reduced sociability and increased anxiety. 37 In both species, the fetal BBB is not fully developed, 38 allowing interference of ABs with fetal development while not crossing the intact maternal BBB.…”

Maternal autoimmunity: risk of neurodevelopmental and neuropsychiatric outcomes

“…Caspr2 antibodies are known to cause acquired neuromyotonia (an autoimmune peripheral nerve disease) and also limbic encephalitis and associated central nervous system syndromes in adults 5. However, CASPR2 is also central to fetal dendritic maturation and aborisation, and so maternal–fetal transfer of these autoantibodies resulting in neurodevelopmental disorders has biological plausibility, and animal models already exist supporting this hypothetical mechanism 6. This publication therefore adds to the literature regarding maternal autoantibodies and neurodevelopmental disorders of offspring.…”

“…Specific IgG targeting neuronal or glial targets, such as CASPR2 antibodies, may result in disruption of neuronal development 6. Alternatively, a more diffuse inflammatory insult involving innate immune activation, activated lymphocytes, polyclonal autoantibodies, elevated cytokines and chemokines could result in a more diffuse inflammatory insult and secondary effects on neuronal and glial development 2.…”

Genetics and epigenetics of autism: A Review

“…Success from a proof‐of‐principle animal study using a similar induced pluripotent stem cells approach but with the intent of treating children with Battenin (CLN3)‐associated retinal degeneration, have been demonstrated by using adenovirus carrying the CLN3 gene Contactin‐associated protein Caspr2 or CNTNAP as a potential drug target: If the antibody against Caspr2 protein could damage the fetal brain during in utero exposure of maternal brain‐reactive antibodies, it is logical to predict that peptides that function to soak up these antibodies could be a protective strategy for mothers with such antibodies. Similar findings with folate receptor alpha (FRα) autoantibodies also suggest that identification of women with such autoantibodies and treating them with high dosage of folic acid might be a feasible treatment strategy .…”