Perinatal stress, brain inflammation and risk of autism-Review and proposal

Abstract

Background Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism “susceptibility” genes have been identified, but “environmental” factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. Discussion We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood–brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with “allergic” or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood–brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. Summary Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients.

Neuropsychological Development in Patients with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency

“…This gives relevance to theories of mitochondrial dysfunction (Rossignol and Frye 2012) and disorders of fatty acid oxidation (Clark-Taylor and Clark-Taylor 2004) as possible neurobiological mechanisms behind autistic dysfunction. In addition, perinatal stress and brain inflammation have been discussed as risk factors (Angelidou et al 2012). Lately, a connection with gut microbiota has been demonstrated (Cryan and Dinan 2012).…”

Pregnancy risk factors in autism: a pilot study with artificial neural networks

“…Many pregnancies and obstetric complications have been correlated in several studies to a greater risk of autism (8)(9)(10)(11). Recent meta-analyses (12,13) underline the role of advanced maternal and paternal age, gestational infections, low birth weight, fetal hypoxia, preterm birth, and labor complications in the pathogenesis of autism.…”

“…Elevated plasma levels of corticotropin-releasing hormone correlate to preterm labor and to anxiety perceived during pregnancy. Acute stress also elevates serum levels of interleukin-6 produced by mast cells, responsible for neuroinflammatory response and disruption of gut-blood barrier and blood-brain barrier permitting neurotoxic molecules to enter the brain, contributing to autism pathogenesis and symptoms (8). After delivery, maternal stress, in particular during the first 6 mo of life of the child, can create important alterations in the early affective mother-child interaction conditioning emotional-behavioral responses of the offspring.…”

“…Recent meta-analyses (12,13) underline the role of advanced maternal and paternal age, gestational infections, low birth weight, fetal hypoxia, preterm birth, and labor complications in the pathogenesis of autism. There is still a debate in international literature about some perinatal risk factors, for example, it is not clear if there is an association between autism and neonatal hyperbilirubinemia (13,14).Many studies have investigated the role of prenatal maternal smoking (15), parental psychiatric conditions (16,17) including baby blues symptoms (8,15), and depressive/anxious traits of parents and siblings (18). Less prominence has been given to maternal stress and stressful life events during pregnancy or in first months after birth (15,19).…”

“…Many studies have investigated the role of prenatal maternal smoking (15), parental psychiatric conditions (16,17) including baby blues symptoms (8,15), and depressive/anxious traits of parents and siblings (18). Less prominence has been given to maternal stress and stressful life events during pregnancy or in first months after birth (15,19).…”