Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system

Neuroplasticity of children in autism spectrum disorder

“…Minocycline inhibits microglia activation and may alleviate ASD-like behavior and improve neurogenesis ( 131 ). The gut microbiome is also an important regulator of microglia and ASD-like social behavior ( 132 ). Microbial interventions, including diet, probiotics, antibiotics, and fecal transplants, as well as immunomodulatory therapies such as cytokine blockade during preconception, pregnancy, and the postpartum are currently improving neurodevelopment, behavioral patterns, and gastrointestinal health in individuals with autism ( 133 ).…”

Etiologies underlying sex bias in autism spectrum disorder: a narrative review of preclinical rodent models

“…High levels of air pollution, particularly during development [59,60], and maternal stress (MS) during gestation [61,62] have been linked to an increased risk of ASD. Smith et al investigated the combined effects of these two risk factors and found that prenatal exposure to air pollution-specifically diesel exhaust particles (DEP)-along with MS in mice led to sociability deficits exclusively in male offspring [63]. These behavioral impairments were paralleled by alterations in microglial morphology and gene expression, with DEP/MS exposure resulting in a hyper-ramified microglial phenotype in male but not female animals.…”

“…Here, we explore the potential mechanisms contributing to the sex-biased prevalence disparity in ASD using various preclinical models (Table 1). While preclinical rodent models of ASD cannot fully replicate the spectrum of human ASD phenotypes [8], potentially due to differences in brain structures and developmental trajectories [9], they remain invaluable for gaining mechanistic Chd8 +/N2373K Sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles [40] Fmr1 KO Sexually dimorphic upregulation of ASD risk genes (male↑: Ctnnb1 a and Grin1 a , female↑: Homer1 a , Ptgs2 a , Drd1 a , Pik3ca b , and Csnk1g1 b ) [44] Microglial abnormalities Cntnap2 KO Activated morphology and phagocytosis of synaptic structures in male microglia [58] DEP/MS Hyper-ramified phenotype in male microglia [63] Hormones VPA-induced ASD mouse model Lower levels of TH expression in the AVPV of male mice [70] Placenta-specific Akr1c14 KO Male mouse-specific abnormalities in cerebellar white matter [75] Escape from X chromosome inactivation Prenatal stress model Placental OGT expression levels are twice as high for female fetuses as for male fetuses; this results in sexually distinct gene expression in trophoblasts through epigenetic modulation by histone methylation [79,80] Integrated stress response pathway MIA (Poly[I:C]) Hyperactivation of the ISR pathway in male MIA offspring, resulting in reduced nascent protein synthesis in the brain [85] Immune pathways Prenatal GBS infection Heightened levels of pro-inflammatory cytokines and chemokines such as IL-1β and CINC-1/CXCL1 in male fetuses [98] MIA (LPS) Male MIA offspring exhibit heightened cortical hypoxia, reduced mitosis of radial glial cells, disrupted E/I balance within the brain, severe placental necrosis, elevated inflammation, and reduced placental growth [99] MIA (two-hit model) The anti-inflammatory cytokines IL-10 and TGF-β1 are decreased in male offspring but increased in female mice [100] ↑: upregulated, a : high-confidence risk genes for ASD, b : suggestive risk genes for ASD. ASD, autism spectrum disorder; Shank3, SH3 and multiple ankyrin repeat domains 3; KO, knockout; mGluR5, metabotropic glutamate receptor 5; Chd8, chromodomain helicase DNA-binding protein 8; Fmr1, fragile X mental retardation 1; Ctnnb1, catenin beta 1; Grin1, glutamate ionotropic receptor NMDA type subunit 1; Homer1 , homer scaffold protein 1; Ptgs2 , prostaglandin-endoperoxide synthase 2; Drd1 , dopamine receptor D1; Pik3ca , phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; Csnk1g1, casein kinase 1 gamma 1; Cntnap2, contactin-associated protein 2; DEP/MS, diesel exhaust particles and maternal stress; VPA, valproic acid; TH, tyrosine hydroxylase; AVPV, anteroventral periventricular nucleus; Akr1c14 , aldo-keto reductase family 1 member C4; OGT, O-linked-N-acetylglucosamine transferase; MIA, maternal immune activation; poly(I:C), polyinosinic:polycytidylic...…”