Potential Cross Talk between Autism Risk Genes and Neurovascular Molecules: A Pilot Study on Impact of Blood Brain Barrier Integrity

Abstract

Autism Spectrum Disorder (ASD) is a common pediatric neurobiological disorder with up to 80% of genetic etiologies. Systems biology approaches may make it possible to test novel therapeutic strategies targeting molecular pathways to alleviate ASD symptoms. A clinical database of autism subjects was queried for individuals with a copy number variation (CNV) on microarray, Vineland, and Parent Concern Questionnaire scores. Pathway analyses of genes from pathogenic CNVs yielded 659 genes whose protein–protein interactions and mRNA expression mapped 121 genes with maximal antenatal expression in 12 brain regions. A Research Domain Criteria (RDoC)-derived neural circuits map revealed significant differences in anxiety, motor, and activities of daily living skills scores between altered CNV genes and normal microarrays subjects, involving Positive Valence (reward), Cognition (IQ), and Social Processes. Vascular signaling was identified as a biological process that may influence these neural circuits. Neuroinflammation, microglial activation, iNOS and 3-nitrotyrosine increase in the brain of Semaphorin 3F- Neuropilin 2 (Sema 3F-NRP2) KO, an ASD mouse model, agree with previous reports in the brain of ASD individuals. Signs of platelet deposition, activation, release of serotonin, and albumin leakage in ASD-relevant brain regions suggest possible blood brain barrier (BBB) deficits. Disruption of neurovascular signaling and BBB with neuroinflammation may mediate causative pathophysiology in some ASD subgroups. Although preliminary, these data demonstrate the potential for developing novel therapeutic strategies based on clinically derived data, genomics, cognitive neuroscience, and basic neuroscience methods.

Prediction of acute kidney injury after cardiac surgery with fibrinogen-to-albumin ratio: a prospective observational study

“…In inflammatory situations, there is an upregulation of fibrinogen, which initiates the recruitment of cells involved in inflammation and platelets. Additionally, it activates endothelial cells, contributing to prolonged vascular inflammation, and resulting in platelet aggregation and leakage in the vasculature ( 35 ). In various diseases, both fibrinogen and albumin have been identified as important prognostic indicators, according to several studies ( 36 , 37 ).…”

PlexinA1-deficient mice exhibit decreased cell density and augmented oxidative stress in parvalbumin-expressing interneurons in the medial prefrontal cortex

“…Both studies discuss the possibility of impairment in the developmental migration of interneurons. Since Nrp2 functions as a coreceptor for Sema3F and interneuron-specific Sema3F KO mice exhibit the decrease of interneuron number in hippocampus ( Li et al, 2019 ), the decreased interneuron density in hippocampus of Nrp2 KO mice may be in part caused by increased oxidative stress, microglial activation, neuroinflammation and so on due to the disruption of blood brain barrier ( Jagadapillai et al, 2022 , Li et al, 2019 ). In another study, siRNA-mediated MICAL1 knockdown decreased the expression of nuclear factor erythroid 2-related factor 2 and both anti-apoptotic factor and autophagy-related proteins, and increased the expression of proapoptotic factors in oligodendrocytes cultured with hydrogen peroxide in an in vitro spinal cord injury model ( Xu et al, 2021 ).…”

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

“…IL-1β destroys the BBB and consequently facilitates the infiltration of immune system cells in the central nervous system [ 49 ]. It also determines an increased expression of chemokines and stimulates the migration of leukocytes into the cerebral parenchyma.…”