Stimulation of the medial septum diagonal band of broca rescues learning and memory deficits in Fmr1 KO mice

Fragile X Syndrome (FXS), the most common inherited cause of intellectual disability and a leading monogenic cause of autism, arises from the loss of Fragile X Messenger Ribonucleoprotein ( Fmr protein), leading to synaptic and cognitive dysfunction. Here, we demonstrate that the frequency-specific electrical stimulation of the medial septum/diagonal band of Broca (MSDB) can restore cognitive and synaptic impairments in Fmr1 knockout mice, a validated model of FXS. Thirty minutes of 35 Hz MSDB stimulation significantly improved subsequent recognition memory, sociability, spatial learning, and fear memory, with recognition memory enhancements persisting for up to 7 days after daily 30 min stimulations for 10 days. Electrophysiological recordings revealed that MSDB stimulation restored basal synaptic transmission and facilitation, and long-term potentiation in hippocampal CA1 neurons. These findings demonstrate that frequency-specific MSDB stimulation can re-engage dysfunctional hippocampal circuits and restore cognitive function in FXS, offering a promising non-pharmacological therapeutic strategy for neurodevelopmental disorders.