• First IREB2-mutated mouse model (Ireb2D826V/D826V) recapitulates NDCAMA-like neurobehavioral deficits, including impaired spatial learning and memory and reduced motor activity.
• The D826V mutation destabilizes IREB2 protein, leading to dysregulated iron metabolism, synaptic dysfunction (impaired LTP, altered PPF), and neuroinflammation (microglial activation).
• Mechanistic link between IREB2 instability and neurodegeneration via synaptic failure and neuroinflammation, providing a platform for testing iron-modulating therapies.
• Establishes a valuable model for studying iron metabolism-driven neurodegeneration and potential therapeutic targets for NDCAMA and related disorders.