Zinc Ion Dyshomeostasis in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with significant social, communicative, and behavioral challenges, and its prevalence is increasing globally at an alarming rate. Children with ASD often have nutritional imbalances, and multiple micronutrient deficiencies. Among these, zinc (Zn²⁺) deficiency is prominent and has gained extensive scientific interest over the past few years. Zn²⁺ supports numerous proteins, including enzymes and transcription factors, and controls neurogenesis and cell differentiation. It modulates synaptic transmission and plasticity by binding to receptors, ion channels, and transporters. These interactions are crucial as changes in these processes may contribute to cognitive and behavioral abnormalities in neurodevelopmental disorders, including ASD. Notably, mutations in genes linked to ASD result in Zn²⁺ dyshomeostasis, altering pivotal biological processes. Additionally, Zn²⁺ promotes gut health by maintaining gut wall integrity, preventing inflammation and leaky gut, translocation of gut bacteria and their metabolites into systemic circulation, and supporting cognitive processes via the gut-brain axis. Zn²⁺ deficiency during pregnancy alters gut microbiota composition, induces pro-inflammatory cytokine production, may affect neuronal functioning, and is associated with ASD etiology in offspring and exacerbation of autistic traits in genetically predisposed children. This review focuses on Zn²⁺ dyshomeostasis, discussing various Zn²⁺-dependent dysfunctions underlying distinct autistic phenotypes and describing recent progress in the neurobiology of ASD in human and animal models. Comprehensive research on the physiological processes altered by Zn²⁺ deficiency is crucial for designing preventive and innovative therapeutic measures for this disorder.