Microglia-specific genetic factors in autism spectrum disorder etiology

Abstract

Autism spectrum disorder (ASD) is a heritable condition that is associated with microglial activation and synaptic dysfunction. Microglia are the brain's resident immune cells in the brain which have been implicated in ASD pathology due to their role in synaptic pruning. Papers were selected based on inclusion criteria: 1) data on microglial genes, 2) ASD condition, 3) English language, and 4) genetic data available. The initial search strategy generated 372 articles from MEDLINE, Embase, Web of Science, and PsycInfo, after screening, 28 studies were included. Study design subsections were separated into 1) environmental, 2) experimental, and 3) case-control studies. CX3C motif chemokine receptor 1 (CX3CR1) and phosphatase and tensin homolog (PTEN) were implicated in the greatest number of studies with direct reference to microglial involvement. Studies screened predominantly supported the connection between microglial genetic variations and ASD symptomology: 13 experimental and environmental studies supported the ASD-microglial genetic connection and 4 were partially supportive; 8 human casecontrol studies were supportive and 2 were partially supportive. However, there was no consensus among studies regarding whether microglial up or down-regulation led to ASD symptomology. This review presents multiple novel microglial-genetic avenues such as the cyclical activation of the CX3CR1 through regionalized neural cytokine expression, the use of Gc macrophage activating factor (GcMAF) to normalize overactivated carbonyl reductase 2 (CBR2), the extensive effect of factors contributing to and resulting from maternal immune activation (MIA), and discrepancies between murine and human studies. These connections contribute to the web of ASD etiology and present targets for the development of ASD symptom management therapeutics.