Table 3.
Summary of findings on maternal immune activation models with a behavioral phenotype exhibiting face validity for compulsions, tics, hyperactivity and cognitive abnormalities observed in attention deficit hyperactivity disorder.
| Type of immunogenic exposure | Species | Stage of developmental period | Behavioral phenotype with face validity for TS, OCD, or ADHD | Pathological and other findings |
|---|---|---|---|---|
| TLR4 agonists (LPS) | ||||
| Intraperitoneal single injection of LPS 100 μg/kg (164) | Wistar rats | GD 9.5 (intermediate gestational period) | Increased number of stereotyped movement episodes (grooming) | Increased protein levels of neuron-specific enolase in hippocampus and decreased levels of TGF-β |
| Intraperitoneal single injection of LPS 100 μg/kg (165) | Wistar rats | GD 9.5 (intermediate gestational period) | Increased frequency and time of head washing episodes and total self-grooming | Dopaminergic hypoactivity decreased levels of homovanillic acid [HVA, dopamine metabolite] and dopaminergic turnover rate |
| Subcutaneous injection of LPS 500 μg/kg every other day (166) | Wistar rats | From GD 14 to 20 (late gestational period) | Impaired performance in the neurogenesis-dependent novel object recognition test | Persistent microglial activation and downregulated expression of TGFβ1 in adult hippocampus and decrease in neurogenesis of the dentate gyrus |
| Intraperitoneal injection of LPS 50 or 25 μg/kg (167) | CD-1 mice | GD 15-17 (late gestational period) | Progressive age-related decline of spatial learning and memory on the six-radial arm water maze (3–22 months of age) | Decreased levels of histone acetylation and syntaxin-1 and increased levels of synaptotagmin-1 in the dorsal hippocampus |
| Intraperitoneal injection of LPS 250, 100, or 50 μg/kg (168) | C57Bl/6JOlaHsd mice | GD 15-17 (late gestational period) | Reduced performance in a T-maze learning task | Pro-inflammatory response in fetal microglia, increased proinflammatory activation and decreased BDNF of hippocampal microglia in response to re-challenge with LPS |
| Intraperitoneal injection of LPS 120 μg/kg (169) | C57BL/6J mice | GD 17 (late gestational period) | Failure to discriminate the novel arm from the familiar one on Y-maze test when exposed also to dietary n-3 PUFA deficiency and deficits in novel object recognition test (spatial memory) | Increased expression of IL-6, TNFα, IL-1β, and IL-10; decreased cFos expression in the dentate gyrus (revealed by dietary n-3 PUFA deficiency) |
| Intraperitoneal injection of LPS 50 μg/kg (170) | C57BL/6 mice | Postnatal days 3 and 5 | Spatial cognitive impairment on the Morris Water Maze | Dysregulated H4K12 (histone) acetylation and impaired c-Fos gene expression in the hippocampus following training |
| TLR4 agonists (LPS) | ||||
| Intravenous injection of Poly-I:C (5 mg/kg) (171) | C57BL/6 mice | GD 17 (late gestational period) | Alterations in the locomotor and stereotyped behavioral responses to acute apomorphine treatment in both sexes. Impaired attentional shifting (abnormally enhanced latent inhibition effect) in males | Sex-specific reduction in dopamine, glutamate, GABA and glycine contents in the prefrontal cortex and hippocampus |
| Intravenous injection of Poly-I:C (2 mg/kg) (172) | Nurr1-deficient mice | GD 17 (late gestational period) | Additive MIA and genetic effects on increased spontaneous locomotor hyperactivity in the open field test, disruption of pre-pulse inhibition of the acoustic startle reflex, abnormally enhanced latent inhibition effect, and defective sustained visual attention. Independent effects of MIA on working memory deficits | Synergistic MIA/genetic effects in the disruption of D2R expression in the core and shell subregions of the nucleus accumbens and in the decrease and increase in tyrosine-hydroxylase and COMT density in the medial prefrontal cortex |
| Intravenous injection of Poly-I:C (4 mg/ml//kg) (173) | Rats | GD 15 (late gestational period) | Loss of latent inhibition and excessive sensitivity to the activating effects of amphetamine which emerged in a sex- and behavior-specific manner (earlier in males) | Aberrant postnatal brain development of the hippocampus, the striatum, the prefrontal cortex and lateral ventricles (delayed onset of pathology in females) |
| Intravenous injection of Poly-I:C (8 mg/kg) (174) | Harlan Sprague-Dawley rats | GD 14 (intermediate gestational period) | Decrease in the rate of route-based learning when visible cues were unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males; excessive sensitivity to the activating effects of amphetamine | |
| Intraperitoneal injection of Poly-I:C (5 mg/kg) (175) | CD1 mice | GD 9.5 (intermediate gestational period) | Increased head-twitch response induced by the 5-HT2A receptor agonist DOI in adult offspring mice | Increased density of 5-HT2A receptors in the frontal cortex of adult offspring mice |
| Intranasal inoculation of Influenza A H3N2 virus (different doses) (176) | BALB/c mice | GD 9 (intermediate gestational period) | Dose-dependent alterations in social and aggressive behaviors in male and female offspring and increases in locomotor behaviors particularly in male offspring | Reduced oxytocin and serotonin levels in male and female offspring and sex-specific changes in dopamine metabolism. Changes in catecholaminergic and microglia density in brainstem tissues of males offspring only |
| Subcutaneous injection of Poly-I:C (2, 4, 8 mg/kg) (177) | Wistar-Hannover rats | GD 9 & 15 (intermediate & late gestational period) | Decreased amphetamine-induced locomotor responses in offspring experiencing weight loss | Induction of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6 and of the anti-inflammatory cytokine IL-10 in maternal blood and in fetal central nervous system. No difference in microglia activation. |
| Intravenous injection of Poly-I:C (8 mg/kg) (178) | Harlan Sprague-Dawley rats | GD 17 (late gestational period) | Decreased startle in males and decreased startle and increased prepulse inhibition of acoustic startle in females. Reduced cued conditioned freezing in males. Impaired Morris water maze hidden platform acquisition and probe performance in both sexes. | |
| Intravenous injection of Poly-I:C (5 mg/kg) (179) | C57/BLJ6 mice | GD 9 & 17 (intermediate & late gestational period) | Partly age-dependent deficits in hippocampus-regulated spatial recognition memory (Y-maze test) | Impaired hippocampal synaptophysin and BDNF expression. |
| Intravenous injection of Poly-I:C (5 mg/kg) (180) | C57/Bl6 mice | GD 15 (late gestational period) | Increased basal locomotor activity regardless of period of injection | Decreased brain volume, mainly for posterior brain structures |
| Intravenous injection of Poly-I:C (4 mg/kg) (181) | Sprague-Dawley rats | GD 12.5 (intermediate gestational period) | Impaired prepulse inhibition of the auditory startle reflex despite preserved performance on the signaled probability sustained attention task | |
| Intraperitoneal injection of Poly-I:C (20 mg/kg) (182) | C57/BLJ6 mice | Increased basal locomotor activity during the early life period (postnatal day 7) | ||
| TLR2 agonists (Streptococcus) | ||||
| Group A Streptococcus antigen 1.2 mg (183) | Male Lewis rats | Postnatal 5 weeks + 2 boosts after 14 and 28 days | Increased number of stereotyped behaviors (induced grooming). Impaired food manipulation and beam walking | Antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia. IgG reacted with tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling in SK-N-SH neuronal cells |
| Purified IgG from GAS rats as obtained in (183, 184) | Male Lewis rats | Postnatal 5, 7 and 9 weeks | Similar changes as in (183) + increased number of marbles buried on the Marble Burying Test | IgG deposits in the striatum of infused rats colocalized with specific brain proteins such as dopamine receptors, the serotonin transporter and other neuronal proteins |
| Subcutaneous injection of monoclonal anti-streptococcus IgM and IgG2a antibodies 6.25 or 12.5 μg (185) | Balb/c mice | Adulthood | IgM antibodies: dose-dependent increases in repetitive stereotyped movements, including head bobbing, sniffing, and intense grooming | IgM antibodies: increased Fos-like immunoreactivity in regions linked to cortico-striatal projections involved in motor control, including subregions of the caudate, nucleus accumbens, and motor cortex. |
| Intraperitoneal injection of 100 μL of serotype Ia Group B Streptococcus (GBS), 108-109 CFU (186–188) | Lewis rats | GD 17-19 (late gestational period) | IgG antibodies: increases in ambulatory activity and vertical activity but not stereotypies Increased spontaneous locomotor activity and worse performance on the Rotarod test (forced motor activity) in females (adulthood). Impaired prepulse inhibition of the auditory startle reflex. | Reduction in the thickness of white matter structures, namely the corpus callosum and the external capsule.Male—but not female—fetuses presented increased levels of IL-1β; fetuses from both sexes increased levels of TNF-α |
The table presents exclusively studies that were published between 2010 and 2019.
TS, Tourette syndrome; OCD, obsessive-compulsive disorder; ADHD, attention deficit hyperactivity disorder; TLR, toll-like receptor; LPS, lipopolysaccharide; GD, gestation day; TGF-β, transforming growth factor-β; BDNF, brain-derived neurotrophic factor; Ig, immunoglobulin; PUFA, polyunsaturated fatty acids; Poly I:C, Polyinosinic:polycytidylic acid; GABA, gamma-aminobutyric acid; MIA, maternal immune activation; D2R, dopamine D2 receptor; 5-HT, 5-hydroxytryptamine; DOI, 2,5-dimethoxy-4-iodoamphetamine; TNF, tumor necrosis factor; IL, interleukin; TNFR, tumor necrosis factor receptor; OCS, obsessive-compulsive symptoms; CCL3, Chemokine (C-C motif) ligand 3; CXCL8, chemokine (C-X-C motif) ligand 8; MCP-1, Monocyte Chemoattractant Protein-1; IP10, Interferon gamma-induced protein 10; TH, T-helper; NK, Natural Killer; DAT, dopamine transporter; TSPO-VT, translocator protein distribution volume; PET, positron emission tomography.