Ion Channel Dysregulation in Neurodevelopmental Disorders: Mechanisms, Models, and Therapeutic Advances

Ion channels are fundamental to neuronal excitability, synaptic transmission, and the coordinated development of brain circuits. Disruptions in their function-collectively termed ion channelopathies-have emerged as central mechanisms underlying a broad spectrum of neurodevelopmental disorders (NDDs), including epilepsy, autism spectrum disorder, and intellectual disability. This review synthesizes current knowledge on the physiological roles of voltage-gated and ligand-gated ion channels during brain development and elucidates how their genetic and functional dysregulation contributes to disease pathogenesis. We examine key channel families, such as sodium, potassium, calcium, and glutamate/(gamma-aminobutyric acid) GABA receptors, as well as mechanosensitive and polymodal channels including transient receptor potential and Piezo channels, highlighting the molecular mechanisms, pathogenic variants, and circuit-level consequences of their dysfunction. Emerging therapeutic strategies are discussed, spanning subtype-specific small molecule modulators, antisense oligonucleotides, CRISPR-based genome editing, and patient-derived organoid models for precision medicine and drug screening. We also address significant challenges in the field, including cellular heterogeneity, developmental timing, and translational model fidelity. Together, these advances underscore a rapidly evolving landscape in which precision neurogenetics and integrative platforms hold promise for transforming the diagnosis and treatment of ion channel-related neurodevelopmental disorders.