Over the past decade, the success of deep brain stimulation (DBS) to treat motor diseases such as Parkinson's and dystonia has been extended in two directions: it is now being used to treat neuropsychiatric diseases in adults, such as obsessive-compulsive disorder, and Alzheimer's disease (AD), and it is beginning to be applied in children to treat both motor and neuropsychiatric diseases (dystonia and Tourette's, respectively). For example, a pilot study showed that forniceal stimulation in AD patients improves hippocampus-dependent memory tasks and slows cognitive decline, and in rodents, stimulation of the fimbria- fornix (FFx) or entorhinal cortex improves spatial memory, likely by modulating hippocampal theta-gamma oscillation, adult neurogenesis, or both. We have recently shown that forniceal DBS enhances hippocampal learning and memory as well as hippocampal synaptic plasticity and dentate neurogenesis in a mouse model of Rett Syndrome (RTT), the leading cause of intellectual disability in females. Caused mainly by mutations that impair the function of MeCP2, an epigenetic transcriptional modulator whose precise activities are the subject of intensive investigation, RTT manifests in females after the first year of life, causing profound cognitive impairment and a wide range of additional features. Affected children appear healthy at birth and achieve early developmental milestones, but between 12 and 18 months suddenly lose acquired motor, language, and social skills and develop an array of neurological and psychiatric features (hand stereotypies, anxiety, autistic behaviors, seizures, autonomic dysfunction, and motor deficits including dystonia, spasticity, and eventual parkinsonism). Several mouse models, either completely lacking MeCP2 or carrying hypofunctional alleles, reproduce the broad phenotype of the disorder, from early apparent health to regression and development of motor dysfunction, social and cognitive deficits; hippocampus-dependent learning and memory and hippocampal synaptic plasticity are impaired. We have shown that DBS rescues these hippocampal features, but the mechanism of action remains unclear: we hypothesize that multiple mechanisms (e.g., hippocampal neurogenesis, local field potential oscillations, neuromodulators, hippocampal volume, and/or global neural network activity) are at work. In this proposal we will (1) determine the extent of DBS effects in young adult and older animals, the duration of memory benefits, and the optimal frequency of treatments; (2) investigate the possible mechanisms by which DBS benefits RTT mice; and (3) determine whether the memory benefits of forniceal DBS are generalizable to other mouse models of intellectual disability. The data will provide insight into the value of manipulations at the circuit level and will lay the groundwork for new therapeutic approaches to RTT and other childhood disorders causing intellectual disability.

Public Health Relevance

This study will provide insight into how targeted deep brain stimulation (DBS) improves hippocampus- dependent learning and memory in mouse models of Rett syndrome and CDKL5 disorder, the diseases characterized by intellectual disability. Pinpointing the underlying mechanisms of DBS at the system level is critical to the understanding of behavioral changes and will provide a framework for developing future interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS100738-02
Application #
9658596
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Mamounas, Laura
Project Start
2018-04-01
Project End
2022-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030