Translational dysregulation as a mechanistic driver of cognitive, behavioral, and affective phenotypes in FXS and TSC

Neurodevelopmental disorders (NDDs) are characterized by a spectrum of cognitive, behavioral, and affective morbidities, reflecting underlying disruptions in neural circuit development. Emerging evidence implicates translational dysregulation of synaptic proteins as a central mechanistic driver of these disordered phenotypes. Translational dysregulation entails atypical mechanisms of impaired initiation, elongation, and mRNA targeting, causing imbalanced protein synthesis. In NDDs specifically, translation of synaptic proteins is perturbed across developing neurons. Tuberous Sclerosis Complex (TSC) and Fragile X Syndrome (FXS) are notable monogenic NDDs, in which mutations in regulatory genes (Tsc1/Tsc2 in TSC, Fmr1 in FXS) disrupt signaling pathways that converge on mTORC1, PERK, and ERK/MAPK proteins, and result in excessive or insufficient translation of key synaptic proteins. These translational imbalances eventually compromise synapse formation, dendritic spine maturation, and neuronal network connectivity, contributing to deficits in learning, memory, social behavior, and emotional regulation. This review highlights the molecular mechanisms by which aberrant protein synthesis contributes to the cognitive and behavioral manifestations of TSC and FXS. Importantly, we also highlight cell-type-specific mechanisms, illustrating how translational dysregulation differentially impacts distinct neuronal and glial populations to shape behavioral and cognitive outcomes. Understanding the links between translational control and neurodevelopmental outcomes provides critical insights into the pathophysiology of these disorders and informs the development of targeted therapeutic interventions aimed at restoring synaptic protein homeostasis.