Abstract
BackgroundAutism, a childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as autism spectrum disorders (ASD). Though multifactorial in etiology, approximately 10% of ASD are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in BALB/c mice. BALB/c is an albino, laboratory-bred strain of the house mouse and is among the most widely used inbred strains used in animal experimentation.MethodsWe performed our studies in valproic acid (VPA)-treated BALB/c hairless mice, a standard mouse model of ASD. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5 and were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various postnatal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels.ResultsAD-like changes in ceramide content occurred by day one postpartum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with early appearance of cytokine markers (i.e., interleukin [IL]-4, 5, and 13), as well as mast cells in skin and brain. The high levels of interferon (IFN)γ not only in skin, but also in brain likely account for a significant decline in esterified very-long-chain N-acyl fatty acids in brain ceramides, again mimicking known IFNγ-induced changes in AD.ConclusionBaseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both epidermis and neural tissues originate from the embryonic neuroectoderm. These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, suggesting that the atopic diathesis could be extended to include ASD.
Highlights
Autism, a childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as autism spectrum disorders (ASD)
Provocation of a permeability barrier abnormality due to epidermal cytotoxicity in valproic acid (VPA)‐exposed neonatal mice While the expected impact of VPA on the developing mouse brain was apparent at birth [56], prominent, previously unreported, cutaneous scaling was immediately apparent in VPA-exposed, neonatal hairless mice (Fig. 1A)
Though neonatal VPA-exposed mice were too small for instrumental assessments of permeability barrier status, a subtle functional defect could be detected with an electron dense tracer, lanthanum nitrate (Additional file 1: Fig. S2), which serves as a surrogate measure of barrier status [e.g. 73]
Summary
A childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as autism spectrum disorders (ASD). Since cumulative epidemiological and clinical studies have shown that prenatal exposure to VPA is tightly linked to a significant increase in the risk of ASD; i.e., the rate of ASD in the children of VPA-exposed mothers is approximately eight times higher than that of the general population [12, 13], in utero exposure of rodents to VPA has been proposed as a robust animal model of ASD This murine model shows great similarities to human features of ASD, including three core deficits: (i) impaired reciprocal social interaction; (ii) restricted, repetitive and stereotyped patterns of behaviors or interests, and (iii) communication deficits, likely reflecting common neuronal alterations in ASD. The net results in exposed animals and humans include early axonal overgrowth and increased network excitability [6] (Additional file 1: Fig. S1)
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