Altered Neuronal and Circuit Excitability in Fragile X Syndrome

Fragile X syndrome (FXS) results from a genetic mutation in a single gene yet produces a phenotypically complex disorder with a range of neurological and psychiatric problems. Efforts to decipher how perturbations in signaling pathways lead to the myriad alterations in synaptic and cellular functions have provided insights into the molecular underpinnings of this disorder. From this large body of data, the theme of circuit hyperexcitability has emerged as a potential explanation for many of the neurological and psychiatric symptoms in FXS. The mechanisms for hyperexcitability range from alterations in the expression or activity of ion channels to changes in neurotransmitters and receptors. Contributions of these processes are often brain region and cell type specific, resulting in complex effects on circuit function that manifest as altered excitability. Here, we review the current state of knowledge of the molecular, synaptic, and circuit-level mechanisms underlying hyperexcitability and their contributions to the FXS phenotypes. Contractor, Klyachko, and Portera-Cailliau review accumulating evidence of changes in channels, neurotransmitters, synapses, and circuits in Fmr1 knockout mice that ultimately cause hyperexcitability. They propose that such alterations in neuronal and circuit excitability could be exploited to treat Fragile X syndrome.