# Deep brain stimulation in Rett syndrome mice: cognitive effects and their mechanisms

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $346,614

## Abstract

PROJECT SUMMARY/ABSTRACT
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.

## Key facts

- **NIH application ID:** 10134446
- **Project number:** 5R01NS100738-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jianrong Tang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $346,614
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-09-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134446

## Citation

> US National Institutes of Health, RePORTER application 10134446, Deep brain stimulation in Rett syndrome mice: cognitive effects and their mechanisms (5R01NS100738-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10134446. Licensed CC0.

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