Baylor researchers enhance brain function in Rett syndrome mice

Researchers at the Baylor College of Medicine and Texas Children’s Hospital have found that deep brain stimulation targeted to the fornix improves learning and memory in a mouse model of Rett syndrome, demonstrating that electrical stimulation promotes the maturation of newborn neurons into hippocampal neural circuits.

Deep brain stimulation has long served as a treatment for movement disorders and certain forms of depression, but investigators have increasingly focused on its cognitive effects. Scientists at the Duncan Neurological Research Institute at Texas Children’s Hospital examined how targeted electrical impulses alter brain function in intellectual disability disorders, publishing their findings in the Proceedings of the National Academy of Sciences.

The team concentrated on Rett syndrome, a condition where MeCP2 gene deficiency impairs normal brain development. This genetic loss leads to reduced dendritic formation, disrupted synaptic function, and impaired communication between neurons in the hippocampus, a brain region vital for memory storage.

Dr. Jianrong Tang and the Baylor Research Team Trace Neural Circuit Disruptions

Dr. Jianrong Tang, an associate professor of pediatric neurology at Baylor and neuroscientist at the Duncan NRI, has spent years studying how neural circuits support cognitive functions. Working alongside colleagues including Drs. Qi Wang, Bin Tang, Zhenyu Wu, and Huda Zoghbi, Tang investigated how circuit breakdowns drive cognitive difficulties in Rett syndrome mouse models.

We found that the Rett syndrome model showed impaired communication between neurons in the hippocampus. Signal transmission between neurons were disrupted and their ability to strengthen connections, synaptic plasticity, a process important for memory formation, were also altered.

Dr. Jianrong Tang, Baylor College of Medicine

Earlier work by the group established that two weeks of daily deep brain stimulation targeted to the fornix—the pathway connecting the hippocampus to other brain areas—rescued learning and memory performance while increasing the production of new brain cells.

Cellular Mechanisms and the Role of Newly Generated Neurons

To test whether those newly generated neurons were strictly necessary for cognitive recovery, the research team blocked cell production during treatment. Without new neuron creation, the memory improvements disappeared, demonstrating that the cells require adequate maturation time to support cognitive function.

DBS helped restore the morphological structure of newborn neurons that did not have the MECP2 protein.

Dr. Jianrong Tang, Baylor College of Medicine

Beyond structural repairs, the treatment improved communication between neurons and helped rebalance the excitatory and inhibitory signaling, according to the findings.

Molecular Pathways Involving Protein KCC2 and GABAergic Switching

At the molecular level, the team investigated how MeCP2 loss causes these cellular deficits. They found that the loss of MeCP2 reduces the protein KCC2, which normally regulates the functional shift of the neurotransmitter GABA from excitatory to inhibitory during early development.

If KCC2 is not functioning properly then GABAergic switching from excitation to inhibition is delayed. As a result, new born neuron maturation is postponed, which may hinder learning and memory. We found that activating KCC2 in the Rett syndrome model mimicked the DBS effect and improved memory performance.

Dr. Jianrong Tang, Baylor College of Medicine

Tang emphasized that these observations remain confined to animal models. Determining whether comparable therapeutic strategies prove safe and effective for human patients requires additional clinical study.

By identifying how neural circuit stimulation, neuron maturation and molecular signaling interact, we have provided a foundation for exploring new strategies to improve cognitive function in Rett syndrome and, hopefully, other IDDs.

Dr. Jianrong Tang, Baylor College of Medicine

The study received financial backing from the National Institute of Neurological Disorders and Stroke, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, core facilities at the Duncan NRI, the Ting Tsung and Wei Fong Chao Foundation, and the Cockrell Family Foundation.