Background: Fragile X syndrome (FXS) is the most common form of monogenic hereditary cognitive
impairment, including intellectual disability, autism, hyperactivity, and epilepsy.
Methods: This article reviews the literature pertaining to the role of synaptic dysfunction in FXS.
Results: In FXS, synaptic dysfunction alters the excitation-inhibition ratio, dysregulating molecular and cellular
processes underlying cognition, learning, memory, and social behavior. Decades of research have yielded important
hypotheses that could explain, at least in part, the development of these neurological disorders in FXS patients.
However, the main goal of translating lab research in animal models to pharmacological treatments in the
clinic has been so far largely unsuccessful, leaving FXS a still incurable disease.
Conclusion: In this concise review, we summarize and analyze the main hypotheses proposed to explain synaptic
dysregulation in FXS, by reviewing the scientific evidence that led to pharmaceutical clinical trials and their