SHANK3 is a postsynaptic scaffolding protein that orchestrates dendritic spine and synapse formation, maturation, and maintenance 1. It functions as a central hub interconnecting glutamate receptors (NMDA, AMPA, and metabotropic) to the actin-based cytoskeleton through interactions with GKAP/PSD-95 and HOMER complexes, thereby regulating synaptic transmission and plasticity 1. SHANK3 controls actin dynamics through interactions with Arp2/3 and WAVE1 complexes, influencing dendritic spine structure and growth cone motility 2. Haploinsufficiency of SHANK3 causes Phelan-McDermid syndrome, characterized by developmental delay, language impairment, and autistic behaviors 3. SHANK3 mutations are prominently associated with autism spectrum disorder (ASD), representing a highly penetrant monogenic risk factor 4. Recent findings reveal SHANK3 dysfunction impairs glutamate signaling and myelination in oligodendrocytes, suggesting pathways beyond neuronal synapses 5. In ASD models, aberrant Wnt-glycolysis signaling in the anterior cingulate cortex contributes to social deficits through disrupted synaptic maturation 6. SHANK3 mutations affect both local and global brain connectivity patterns, with behavioral consequences including social impairments, learning deficits, and repetitive behaviors 4. These findings establish SHANK3 as a critical regulator of synaptic architecture and function underlying neurodevelopmental disorders.