iTBS Improves Behavioral Abnormalities and Synaptic Defects in Fmr1 KO Rats by Regulating the Autophagy Pathway

Synaptic dysfunction resulting from abnormal autophagy may contribute to the pathogenesis of fragile X syndrome (FXS). Intermittent theta burst stimulation (iTBS) is a novel magnetic stimulation mode that has shown promising therapeutic potential in various neurological disorders. However, the therapeutic effects of iTBS on FXS-related behavior abnormality and its underlying mechanism remain unclear. In this study, we investigated whether iTBS could ameliorate behavioral abnormalities and synaptic dysfunction associated with FXS by modulating the autophagy pathway. This study utilized Fmr1 knockout (KO) rats as experimental models. The rats underwent a 2-week iTBS intervention, and behavioral changes were assessed through a series of behavioral tests. Electrophysiological recordings were performed to examine alterations in hippocampal neural oscillations. Golgi staining and Western blotting were utilized to evaluate changes in synaptic structure and synaptic related proteins, while Western blotting and immunofluorescence were employed to assess alterations in autophagy-related proteins. Our results demonstrated that iTBS significantly improved behavioral deficits in Fmr1 KO rats. Furthermore, iTBS effectively attenuated abnormally heightened hippocampal theta-gamma phase-amplitude coupling in these rats. Treatment with iTBS also led to sustained improvements in synaptic defect, along with the restoration of CaMKK2 activity and autophagy defect in the hippocampus of Fmr1 KO rats. These findings underscored the beneficial effects of iTBS on aberrant behavior and synaptic defects in Fmr1 KO rats, highlighting the involvement of the CaMKK2-dependent autophagy pathway in this process and suggesting the potential therapeutic value of iTBS for individuals with FXS.