Table 3.

Preclinical studies of maternal autoantibodies and ASD-like pathology.

Pre-clinical model details	Summarized findings	References
Mouse model
Sera from 1 ASD mother (auto-Ab+) and 4 TD mothers injected into pregnant MF1 mice at varied time points. Offspring behaviors and cerebellar chemistry measured with standard behavioral tests and MRS	ASD-sera exposed offspring exhibited: ↓ reflexes ↓ exploration ↓ spatial orientation ↓ creatine and choline concentrations in cerebellum No impairments in memory	Dalton et al., 2003
Non-human primate model Purified IgG from separately pooled from 21 ASD and 7 TD maternal sera, measured for presence of auto-Abs. 4 Rhesus macaques were injected IV with auto-Ab+ IgG from ASD maternal sera and 4 were injected with auto-Ab- IgG from TD maternal sera at GD 27, 41, and 55. Behaviors assessed at preweaning and postweaning time points.	ASD-IgG exposed offspring exhibited: ↑ whole-body stereotypies ↑hyperactivity No significant differences seen in social behaviors	Martin et al., 2008
Mouse model Purified IgG from separately pooled from 63 ASD and 63 TD maternal sera, injected IP into 26 pregnant C57Bl/6J mice total, 13 dams per group, at E13-E18. Offspring from untreated and from saline injected mice included as negative controls. Several behavioral and neurodevelopmental outcomes measured.	ASD-IgG exposed offspring exhibited: ↑ anxiety, startle, and hyperactivity ↑ Iba1 staining indicating microglia activation in E18 embryos ↑ BDNF at adolescence Social deficits seen at adulthood IL-12 detectable in E16 embryos	Singer et al., 2009
Mouse model Purified IgG from pooled from 3 ASD maternal sera positive for 37 kDa and 73 kDa fetal brain protein reactivity. Purified IgG also pooled from 3 TD maternal sera absent of reactivity. Single IV injection of purified IgG per group given to pregnant C57Bl/6J mice at GD 12, saline given as negative control. Offspring assessed for behavioral abnormalities and alterations in neurodevelopment.	ASD-IgG exposed offspring exhibited: ↓ weight and body length ↓ sensory and motor development prior to weaning ↑ anxiety ↑ vocalizations during separation-induced stress in males at PND8 Social deficits trended in males but did not reach significance No differences seen in stereotypical behaviors No differenced seen in numbers of CA1 hippocampal neurons	Braunschweig et al., 2012b
Non-human primate model Purified IgG from ASD maternal sera positive for 37 kDa and 73 kDa autoAbs and purified IgG from TD maternal sera absent of reactivity injected IV into two groups of pregnant Rhesus macaques at GD 30, 44, 58, 72, 86, and 100.	ASD-IgG exposed offspring exhibited: ↑ maternal protectiveness during pre-weaning stage ↑ inappropriate and frequency of social approach in juveniles ↑ brain volume in males compared with controls, mainly white matter and most profoundly in the frontal lobes.	Bauman et al., 2013
Mouse model Purified IgG from ASD maternal sera positive for autoAbs or from TD maternal sera absent of reactivity was injected directly into cerebral ventricles of E14 embryonic Swiss Webster mice. Behaviors measured with battery of behavioral assays	ASD-IgG injected adult offspring exhibited: ↑ grooming ↑ marble burying No differences in social approach, however ASD-IgG mice had↑ time spent with novel object compared to mice injected with TD-IgG	Camacho et al., 2014
Mouse model Biotinylated IgG from ASD maternal sera positive for 37 kDa and 73 kDa fetal brain protein reactivity or from TD maternal sera absent of reactivity was injected directly into cerebral ventricles of E14 or E16 embryonic Swiss Webster mice. Brain reactivity and quantification assessed with IHC and stereology.	Brain from ASD-IgG injected embryos exhibited: Reactivity to RG cells (neural stem cells) in VZ ↑proliferative Pax6+ RG cells in the SVZ ↑mitotic precursor cells in the SVZ of the ganglionic eminence (a neurodevelopmental structure that guides cell and axon migration) RG cells translocated much earlier than control mice ↑ brain weight and rostro-caudal length ↑somal volume in neurons	Martinez-Cerdeno et al., 2016
Mouse model Purified IgG from ASD maternal sera positive for 37 kDa and 73 kDa fetal brain protein reactivity or from TD maternal sera absent of reactivity was injected directly into cerebral ventricles of E14 embryonic Swiss Webster mice. Changes in dendritic arbor and spine population assessed with Golgi method and Neurolucida.	Adult brain from ASD-IgG injected embryos showed: ↓ length and volume of dendritic spines on neurons of the frontal cortex ↓ total number of spines on neurons in frontal cortex ↓ total number of spines on neurons in occipital cortex ↓ spine density of apical dendrites, and ↓ number of mature spines on basal and apical dendrites in occipital cortex	Ariza et al., 2017
Mouse model Mixtures of 21 synthesized epitopes of LDH-A, LDH-B, STIP1, and CRMP1 (fetal brain target peptides) plus adjuvant were injected SC 5 times into dams prior to mating (MAR-ASD). Control females injected SC with saline plus adjuvant. Maternal sera tested for verification of endogenous autoAb production. Offspring behaviors measured with behavioral assays	Epitope-specific antibodies were successfully produced and persisted in dams through end of lactation MAR-ASD offspring exhibited: ↑ weight and head width ↑ repetitive behaviors ↓ social behaviors, including male-female social interactions	Jones et al., 2018

ASD, autism spectrum disorder; autoAb, autoantibody; MRS, magnetic resonance spectroscopy; IgG, immunoglobulin G; TD, typically developing; IV, intravenous; GD, gestational day; IP, intraperitoneal; Iba1, Ionized calcium binding adaptor molecule 1; E13, embryonic day 13; BDNF, brain derived neurotrophic factor; IL-12, interleukin-12; IHC, immunohistochemistry; RG cells, radial glial cells; VZ, ventricular zone; SVZ, subventricular zone; LDH, lactate dehydrogenase; STIP1, stress-induced phosphoprotein 1; CRMP1, collapsin response mediator protein 1; SC, subcutaneous.