title: Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice.
abstract: Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnesic rats have demonstrated that DBS targeted to the fimbria-fornix, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder. Such disorders are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We proposed that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP2 (ref. 6), RTT appears by the second year of life in humans, causing profound impairment in cognitive, motor and social skills, along with an array of neurological features. RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity. Here we show that forniceal DBS in RTT mice rescues contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restores in vivo hippocampal long-term potentiation and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT.
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Hao
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Ure
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Huifang
authors.initials: H
authors.lastname: Tao
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Akash J
authors.initials: AJ
authors.lastname: Patel
authors.affiliation: Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Curry
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Rodney C
authors.initials: RC
authors.lastname: Samaco
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Tang
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000150:complications / Q000503:physiopathology / Q000523:psychology / Q000628:therapy; D046690:Deep Brain Stimulation; D004195:Disease Models, Animal; D005239:Fear / Q000502:physiology / Q000523:psychology; D005260:Female; D020712:Fornix, Brain / Q000166:cytology / Q000502:physiology* / Q000503:physiopathology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology* / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D055495:Neurogenesis; D015518:Rett Syndrome / Q000235:genetics / Q000503:physiopathology / Q000523:psychology* / Q000628:therapy*; D065853:Spatial Learning / Q000502:physiology