Abstract
Clinical trials are currently underway to assess the efficacy of forniceal deep brain stimulation (DBS) for improvement of memory in Alzheimer's patients, and forniceal DBS has been shown to improve learning and memory in a mouse model of Rett syndrome (RTT), an intellectual disability disorder caused by loss-of-function mutations in MECP2. The mechanism of DBS benefits has been elusive, however, so we assessed changes in gene expression, splice isoforms, DNA methylation, and proteome following acute forniceal DBS in wild-type mice and mice lacking Mecp2. We found that DBS upregulates genes involved in synaptic function, cell survival, and neurogenesis and normalized expression of ~25% of the genes altered in Mecp2-null mice. Moreover, DBS induced expression of 17-24% of the genes downregulated in other intellectual disability mouse models and in post-mortem human brain tissue from patients with Major Depressive Disorder, suggesting forniceal DBS could benefit individuals with a variety of neuropsychiatric disorders.
Data availability
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RNA-Sequencing data - acute DBSPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE107357).
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Whole-Genome bisulfite sequencingPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE107383).
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RNA-Sequencing data - chronic DBSPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE111703).
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Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE24095).
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Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primatesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE39697).
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Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selectionPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE13539).
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Neuronal activity modifies the DNA methylation landscape in the adult brain.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE30493).
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DNA methylation changes in plasticity genes accompany the formation and maintenance of memoryPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE74971).
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Widespread transcription at neuronal activity-regulated enhancersPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE21161).
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Nuclear RNA-seq of single neurons reveals molecular signatures of activation.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE77067).
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Activity-dependent regulation of inhibitory synapse development by Npas4.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE11261).
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Identification of activity-dependent gene expression profiles reveals specific subsets of genes induced by different routes of Ca(2+) entry in cultured rat cortical neurons.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE6254).
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Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE61887).
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Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE43261).
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Transcriptome profile reveals AMPA receptor dysfunction in the hippocampus of the Rsk2-knockout mice, an animal model of Coffin-Lowry syndrome.Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE22137).
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Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mousePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE80312).
Article and author information
Author details
Funding
National Institutes of Health (5R01NS057819)
- Huda Y Zoghbi
Howard Hughes Medical Institute (HHMI Investigator)
- Huda Y Zoghbi
Robert and Janice McNair Foundation (Student Scholar)
- Amy E Pohodich
Baylor Research Advocates for Student Scientists (Student Scholar)
- Amy E Pohodich
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All research and animal care procedures were approved by the Baylor College of Medicine Institutional Animal Care and Use Committee (approved protocols: AN-1013 and AN-5585). All surgery was performed under isofluorane anesthesia, and every effort was made to minimize pain and suffering.
Reviewing Editor
- Anne E West, Duke University School of Medicine, United States
Publication history
- Received: December 4, 2017
- Accepted: March 22, 2018
- Accepted Manuscript published: March 23, 2018 (version 1)
- Version of Record published: April 18, 2018 (version 2)
Copyright
© 2018, Pohodich et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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