Synaptic disturbance in neurodevelopmental disorders: Perspectives from fragile X and Rett syndromes

Neurodevelopmental disorders (NDDs) are often referred to as "synaptopathies" because many of their behavioral symptoms arise from impaired synaptic development and function. However, the mechanisms that connect synaptic dysfunction to neurological symptoms remain unclear, mainly due to the wide variety of genetic and environmental factors involved in these disorders. Fragile X syndrome and Rett syndrome, two extensively studied monogenic NDDs, provide a unique opportunity to explore these mechanisms at molecular, cellular, and synaptic levels. This review summarizes the current understanding of how synaptic alterations contribute to the neurological symptoms observed in fragile X and Rett syndromes. A comparison of findings from mouse models indicates that an imbalance in local and distal connectivity may serve as a common feature of both disorders.