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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1751-5) contains supplementary material, which is available to authorized users.

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

“…39 Thus, high levels of ABs might not be required to distinguish MCPD from CTLM. 10 Synaptic NMDAR activity is involved in different stages of fetal and neonatal brain development, crucial for ; CTL, n = 16; NR1, n = 14; mean AE SD, unpaired t test, p = 0.0005) showed highly significant differences in total brain volumes. Also, other factors could facilitate maternofetal AB transfer and induce neuropsychiatric disease, such as inflammation, genetic risk loci, placental microstructure, or psychosocial stress ("second hits").…”

“…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. 10 Synaptic NMDAR activity is involved in different stages of fetal and neonatal brain development, crucial for ). (H) Representative brain magnetic resonance imaging (MRI) of CTL and NR1 ABtreated neonates (hippocampal regions highlighted).…”

“…4,5 Murine models of gestational transfer of maternal ABs have already revealed deleterious effects of some antineuronal ABs, for example, anti-NR2B (GluN2B), 6 antifetal brain ABs from mothers of children with ASD, 7,8 and anti-Caspr2 ABs. 9,10 So far, little is known about maternal ABs against the NR1 (GluN1) subunit of the Nmethyl-D-aspartate receptor (NMDAR), although it is among the most frequent anti-neuronal ABs in clinically asymptomatic individuals, with an IgG seroprevalence of 1%. 11,12 This creates a considerable subgroup of pregnancies in which NR1 ABs can be diaplacentally transferred.…”

Maternal thyroid autoimmunity associated with acute‐onset neuropsychiatric disorders and global regression in offspring

“…In humans, maternal interleukin‐6 levels are associated with altered neuronal connectivity and working memory in newborn infants, and elevated maternal mid‐gestational levels of interleukin‐4, interleukin‐5, and interferon‐gamma have been associated with autism in offspring . The transfer of maternal autoantibodies may also be relevant, considering maternal contactin‐associated protein‐2 (CASPR2) and thyroid peroxidase antibodies have been associated with adverse neurodevelopmental and neuropsychiatric outcomes …”

“…contactin-associated protein-2 (CASPR2) and thyroid peroxidase antibodies have been associated with adverse neurodevelopmental and neuropsychiatric outcomes. [21][22][23] It can be hypothesized that maternal immune activation affects neurodevelopment of the offspring in utero by multiple mechanisms, including epigenetic alteration of neurodevelopmental vulnerability genes in the offspring, the direct effect of maternal immune molecules such as proinflammatory cytokines or autoantibodies on neurogenesis and synaptic formation, and priming of microglia affecting synaptic development and potential further activation ex utero by stress or infection. 5,24 We hypothesize that such fetal brain priming (epigenetically or immunologically) provides a plausible explanation for the infection provoked relapsing-remitting course evident in the majority of the cases described in this report, and a different theoretical mechanistic model of what has been called paediatric acute neuropsychiatric syndrome.…”