Hippocampal dysfunction and cognitive impairment in Fragile-X Syndrome

Fragile-X Syndrome (FXS) is the most common form of inherited intellectual disability and the leading genetic cause of autism spectrum disorder. FXS is caused by transcriptional silencing of the Fragile X Mental Retardation 1 (Fmr1) gene due to a CGG repeat expansion, resulting in the loss of Fragile X Mental Retardation Protein (FMRP). FMRP is involved in transcriptional regulation and trafficking of mRNA from the nucleus to the cytoplasm and distal sites both in pre- and post-synaptic terminals. Consequently, FXS is a multifaceted disorder associated with impaired synaptic plasticity. One region of the brain that is significantly impacted by the loss of FMRP is the hippocampus, a structure that plays a critical role in the regulation of mood and cognition. This review provides an overview of the neuropathology of Fragile-X Syndrome, highlighting how structural and synaptic deficits in hippocampal subregions, including the CA1 exhibiting exaggerated metabotropic glutamate receptor dependent long-term depression and the dentate gyrus displaying hypofunction of N-methyl-d-aspartate receptors, contribute to cognitive impairments associated with this neurodevelopmental disorder.