Neuronal Dysfunction in Fragile X Spectrum Disorders.

Abstract

Fragile X spectrum disorders are a family of allelic syndromes caused by expanded trinucletide CGG repeats in the 5’ untranslated region (UTR) of the FMR1 gene on the X chromosome. The full mutation (greater than 200 CGG repeats) causes Fragile X Syndrome (FXS), the most common monogenic cause of autism and intellectual disability, which results from the absence of the FMR protein. Premutation range repeats (50-200) cause the neurodegenerative disorder Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). As FXS is developmental and is implicated in a host of neuronal phenotypes, and FXTAS is an age-related degenerative disorder characterized by movement symptoms, the field has classically considered the pathogenesis of these two syndromes as separate despite their shared mutation. While the mechanisms of neurodegeneration in FXTAS are likely distinct from those in FXS, recent work suggests younger premutation carriers may have an increased incidence of autistic- and ADHD-like symptoms. The primary hypothesis for this work is that the expanded CGG repeats would impair FMRP translation, which alters FMRP target protein expression, thus causing synaptic dysfunction and alterations in animal behavior. This dissertation describes reduced basal and activity-dependent FMRP expression in premutation model mice (CGG knock-in, CGG KI), which correlates with enhanced protein synthesis-dependent metabotropic glutamate receptor-dependent long term depression (mGluR-LTD). One FMRP target, amyloid precursor protein (APP), expression is altered in CGG KI mouse and FXTAS patient cerebella. These cellular phenotypes are correlated with impaired sensorimotor gating in CGG KI mice. Premutation model neurons also show differential axonal voltage-gated sodium channel expression, and altered homeostatic plasticity. Together, these findings indicate significantly altered neuronal function from the level of protein expression, to synaptic function, to animal behavior in CGG KI mice. These findings suggest that some mechanisms of neuronal dysfunction could be shared between FXS and premutation patients. This dissertation describes numerous novel phenotypes identified in premutation model animals, and encourages consideration of mechanistic overlap across the Fragile X spectrum.