Publication Date
1-1-2023
Journal
Brain Stimulation
DOI
10.1016/j.brs.2023.09.002
PMID
37704033
PMCID
PMC11152200
PubMedCentral® Posted Date
6-5-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Mice, Animals, Rett Syndrome, Brain-Derived Neurotrophic Factor, Deep Brain Stimulation, Vascular Endothelial Growth Factor A, Hippocampus, Neurogenesis, deep brain stimulation, fornix, hippocampus, neurogenesis, fear memory, Rett syndrome
Abstract
BACKGROUND: Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed that forniceal deep brain stimulation (DBS) stimulates hippocampal neurogenesis with concomitant improvements in hippocampal-dependent learning and memory in a mouse model of RTT.
OBJECTIVES: To determine the duration of DBS benefits; characterize DBS effects on hippocampal neurogenesis; and determine whether DBS influences MECP2 genotype and survival of newborn dentate granular cells (DGCs) in RTT mice.
METHODS: Chronic DBS was delivered through an electrode implanted in the fimbria-fornix. We tested separate cohorts of mice in contextual and cued fear memory at different time points after DBS. We then examined neurogenesis, DGC apoptosis, and the expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) after DBS by immunohistochemistry.
RESULTS: After two weeks of forniceal DBS, memory improvements lasted between 6 and 9 weeks. Repeating DBS every 6 weeks was sufficient to maintain the improvement. Forniceal DBS stimulated the birth of more MeCP2-positive than MeCP2-negative DGCs and had no effect on DGC survival. It also increased the expression of BDNF but not VEGF in the RTT mouse dentate gyrus.
CONCLUSION: Improvements in learning and memory from forniceal DBS in RTT mice extends well beyond the treatment period and can be maintained by repeated DBS. Stimulation of BDNF expression correlates with improvements in hippocampal neurogenesis and memory benefits.