Rett and MECP2 duplication syndrome mice have identical malfunction in neural circuits that can be corrected by DBS


HOUSTON – Aug 4, 2016 – Hundreds of genetic mutations that affect myriad signaling pathways can cause autism and other intellectual disabilities. Often, opposite alterations in the same genes can result in remarkably similar clinical symptoms. The neural network mechanisms underlying this intriguing phenomenon remain unexplored.

A paper published this week in “Neuron” from Dr. Huda Y. Zoghbi’s laboratory at the Jan and Dan Duncan Neurological Institute (NRI) at Texas Children’s Hospital and Baylor College of Medicine shows that identical abnormalities in neural circuits might underlie similar features in two distinct genetic syndromes. It was even more exciting that deep brain stimulation (DBS) reversed these circuit malfunctions in mouse models of Rett syndrome and MECP2 duplication syndrome.

The X-linked gene, MECP2, encodes methyl CpG-binding protein, a master regulator of several genes. In 1999, Dr. Zoghbi’s team discovered that loss of MECP2 function causes Rett syndrome. Interestingly, a few years later we learned that extra copies of this gene resulted in a related, yet distinct neurodevelopmental disorder, MECP2 duplication syndrome.

Although structural and functional properties of individual neurons differ in both syndromes, both categories of patients suffer from similar learning and behavioral deficits such as autism and intellectual disability.

“In the end, higher-order learning and behavior does not depend on a single neuron or synapse, but on how well a neural circuit functions, just like a symphony orchestra,” says Dr. Zoghbi, Howard Hughes Medical Investigator, professor at Baylor and director of the NRI at Texas Children’s.

Mammalian brain consists of billions of interconnected neurons that form millions of intricate circuits, each dedicated to a specific function. Hippocampus is the region of the brain involved in learning and memory. To monitor the activity of hippocampal circuits in mouse models of Rett and MECP2 duplication syndromes, researchers generated transgenic mice that expressed fluorescently labeled calcium-sensors that light up in actively firing neurons.

In the brains of normal people, optimal function of the hippocampal circuit relies on asynchronous and sparse firing of individual neurons, which is thought to keep them adaptable to new information. Neural circuits are maintained in this nimble state through a fine balance of excitatory and inhibitory neurons.

In contrast to that, researchers found that neural circuits from Rett and MECP2 duplication syndrome mice had increased synchrony. Further, they found that this hypersynchrony was a result of dysfunctional inhibitory neurons, which were unable to effectively dampen excessive excitation. Excessive synchrony in hippocampal circuit has been reported previously to interfere with normal information processing, disrupt circuit dynamics and hinder learning.

“Electrical circuits in a house can be damaged in many ways – by lightning during a thunderstorm, by frayed or improperly wired cables or if the system is overburdened with too many appliances – leading to a common outcome, electrical fires. Similarly, this study shows that different genetic mutations may disrupt neural circuits in distinct ways, but eventually, they all result in clinically comparable outcomes,” says Zoghbi.

Recently, Zoghbi, Tang and collaborators showed that applying DBS to a specific region of the hippocampus improved learning and memory in Rett syndrome mice. DBS is a nonsurgical treatment wherein a specific region of the brain is stimulated with the aim of regulating abnormal activity and is being used increasingly for many movement disorders.

“However, it was unclear how DBS restored normal brain activity,” said Dr. Hui Lu, postdoctoral researcher at Baylor and the lead author of this study.

In this study, researchers showed that hippocampal DBS reversed the circuit abnormalities in mouse models of Rett syndromes. This provides some insight into how DBS improves learning, memory and cognition.

“This study raises the possibility that other autism and intellectual disability syndromes could, perhaps, also result from excessive synchrony in specific circuits. It would be important to evaluate the circuit properties in other neurological disorders such as Angelman syndrome or Fragile X syndrome because this would open up the possibility of using DBS and maybe other methods of neuromodulation to modify circuit function and potentially improve learning and memory in those disorders as well,” Zoghbi adds.

About Texas Children’s Hospital

Texas Children’s Hospital, a not-for-profit health care organization, is committed to creating a healthier future for children and women throughout the global community by leading in patient care, education and research. Consistently ranked as the best children’s hospital in Texas, and among the top in the nation, Texas Children’s has garnered widespread recognition for its expertise and breakthroughs in pediatric and women’s health. The hospital includes the Jan and Dan Duncan Neurological Research Institute; the Feigin Tower for pediatric research; Texas Children’s Pavilion for Women, a comprehensive obstetrics/gynecology facility focusing on high-risk births; Texas Children’s Hospital West Campus, a community hospital in suburban West Houston; and Texas Children’s Hospital The Woodlands, a second community hospital planned to open in 2017. The organization also created the nation’s first HMO for children, has the largest pediatric primary care network in the country and a global health program that’s channeling care to children and women all over the world. Texas Children’s Hospital is affiliated with Baylor College of Medicine. For more information, go to www.texaschildrens.org. Get the latest news by visiting the online newsroom and Twitter at twitter.com/texaschildrens.