Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity

Amy E Pohodich,Jianrong Tang,Michael Gundry,Hari Yalamanchili,Ying-Wooi Wan,Zhandong Liu,Haijing Jin,Ayush T Raman,Huda Y Zoghbi,Shuang Hao

doi:10.7554/elife.34031

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.

Highlights

Deep brain stimulation (DBS) provides electrical stimulation to the brain through implantation of indwelling electrodes in various specific regions, according to the effect desired (Perlmutter and Mink, 2006)
Deep brain stimulation promotes expression of genes involved in neuronal plasticity To better understand the effects of forniceal deep brain stimulation (DBS) on neuronal processes, we utilized a DBS implantation and stimulation paradigm previously reported by our lab and that uses parameters similar to those used in humans (Figure 1A and B) (Hao et al, 2015)
We found thousands of gene expression differences between wild-type mice that had undergone DBS treatment and those that had been sham-treated; 1025 genes were either increased or decreased at least two-fold by DBS (Figure 1C; Figure 1—source data 1)

Summary

Introduction

Deep brain stimulation (DBS) provides electrical stimulation to the brain through implantation of indwelling electrodes in various specific regions, according to the effect desired (Perlmutter and Mink, 2006). DBS has proven effective in relieving the symptoms of movement disorders, most notably Parkinson’s disease and essential tremor (Benabid et al, 1991; Miocinovic et al, 2013). The safety and efficacy of forniceal DBS to activate the hippocampus is being assessed in human clinical trials as a therapy to slow the cognitive decline resulting from Alzheimer’s disease (Laxton et al, 2010; Lozano et al, 2016; Ponce et al, 2016; Sankar et al, 2015). Animal studies have shown that forniceal stimulation in mice and rats with defects in hippocampal memory markedly improves deficits in hippocampus-dependent memory tasks; these improvements correlated with enhanced circuit function and neurogenesis (Hao et al, 2015; Shirvalkar et al, 2010)

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Results

Conclusion