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

Many brain disorders cause impairments in learning and memory. These include developmental disorders such as Rett syndrome, in which children struggle with learning, as well as diseases of old age such as Alzheimer’s disease. People with these disorders often show changes in a region of the brain called the hippocampus. Named after the Greek word for ‘seahorse’ because of its shape, the hippocampus has a key role in forming new memories. Restoring normal activity in the hippocampus could thus help reduce learning and memory impairments. One way to increase activity in the hippocampus is through a technique called deep brain stimulation (DBS). As the name suggests, DBS involves lowering electrodes deep into the brain to stimulate specific areas of brain tissue. Applying DBS to the fornix, a bundle of nerve fibers that carries information into and out of the hippocampus, improved memory in a mouse model of Rett syndrome. But exactly how DBS produced this improvement is unclear. Pohodich et al. now showed that DBS of the fornix alters gene activity in the mouse hippocampus. To activate a gene, cells first used the gene’s DNA as a template to produce a molecule of RNA. They then used the RNA as a template to produce a protein. Disorders such as Rett syndrome disrupt the efficiency of this process for large numbers of genes. Pohodich et al. showed that stimulating the fornix of mice with Rett syndrome reversed these changes for about a quarter of genes affected in the disorder. DBS also induced changes in thousands of RNA molecules in healthy mice. Many of these come from genes that support communication between nerve cells or that promote the formation of new nerve cells. DBS may have beneficial effects in other disorders too. Pohodich et al. showed that DBS also increases the levels of genes that are decreased in two other intellectual disability disorders, as well as genes that are altered in depression. For DBS to become a viable treatment, clinical trials must establish its safety and efficacy. Such trials are already underway in patients with Alzheimer’s disease. Future trials could include patients with learning impairments, or with depression that has not responded to other treatments.