Modelling fragile X-associated neuropsychiatric disorders in young inducible 90CGG premutation mice

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a preCGG repeat expansion in the FMR1 gene. Individuals with the FMR1 premutation often exhibit neuropsychiatric symptoms before FXTAS onset, leading to the identification of fragile X-associated neuropsychiatric disorders (FXAND). Rodent models of FXTAS show motor impairments, pathological intranuclear inclusions, and heightened anxiety. However, the early onset of neuropsychiatric features and underlying mechanisms remain poorly understood. To address the above issues, we used the doxycycline (dox)-inducible 90CGG mouse model, with transgene activation at two developmental stages: adolescence and young adulthood. Mice were evaluated in a behavioural battery to assess anxiety-like behaviour, exploration, and motor coordination and learning. Next, we conducted a combination of ex vivo extracellular local field potential recordings to measure synaptic physiology and oscillatory activity in the limbic system, particularly in the basolateral amygdala (BLA) and ventral hippocampus (vH) regions. Parvalbumin interneurons and intranuclear inclusions in the amygdala and hippocampus were investigated by immunofluorescence, while mass spectrometry and gene set enrichment were used to identify differentially expressed proteins molecular pathways. Adolescent 90CGG mice displayed early-onset hyperactivity, transitioning to heightened anxiety in young adulthood, coinciding with the accumulation of intranuclear inclusions in the BLA and vH. Electrophysiological analysis revealed augmented gamma oscillations in the vH, emerging during adolescence and persisting in young adulthood. These changes correlated with a reduction in parvalbumin interneurons in these regions, and together likely contribute to enhanced BLA excitability and impaired vH plasticity. Finally, proteomic analysis of the vH revealed altered proteins linked to attention deficit hyperactivity disorder in adolescence and anxiety/depression in adulthood, aligning well with behavioural findings. Importantly, these behavioural, electrophysiological, and cellular alterations were reversible upon transgene inactivation. This study reveals a temporal progression of CGG premutation effects on behaviour, from hyperactivity to heightened anxiety to late onset motor dysfunction. Moreover, these findings provide altered network activity in the limbic system as a putative mechanism in neuropsychiatric features of premutation carriers.