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

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.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.Autism Spectrum Disorders (ASD) are pervasive neurodevelopmental disorders that include autistic disorder, Asperger’s disorder, and Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) [1,2]. ASD are characterized by variable deficits in communication and social skills, a wide range of behavioral and learning problems and stereotypic behaviors. ASD manifest during early childhood and at least 30% of cases present with sudden clinical regression of development around 3？years of age often after acute episodes, such as a viral inf