Forniceal deep brain stimulation improves memory in Rett syndrome mice by promoting the maturation of newborn hippocampal neurons

Deep brain stimulation (DBS) is associated with an increase in hippocampal neurogenesis and memory benefits, but the causal mechanism is unclear. Here, we use a mouse model of Rett syndrome, a severe learning disability syndrome caused by MECP2 loss of function, to find that DBS promotes the maturation and integration of newborn dentate granule cells (DGCs) into the neural circuit. Suppressing hippocampal neurogenesis prevented DBS from improving learning and memory. Newborn methyl-CpG-binding protein 2 (MeCP2)-deficient DGCs in Rett syndrome mice showed attenuated development and synaptic dysfunction, but DBS rescued DGC dendritic arborization, synaptogenesis, and long-term synaptic plasticity. DBS achieves this, at least in part, by increasing the protein level and shifting the phosphorylation of potassium chloride cotransporter 2, thereby restoring the conversion of GABAergic signaling from depolarization to hyperpolarization, a process that is otherwise delayed by MeCP2 deficiency. This study pinpoints one mechanism by which chronic DBS promotes neuronal maturation and enhances memory.