Hundreds of genetic mutations that affect myriad signaling pathways can cause autism and other intellectual disabilities. Often, opposite changes 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 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. Interestingly, 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, Zoghbi’s team discovered that loss of MECP2 function causes Rett syndrome. A few years later, researchers found 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,” said Zoghbi, a 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,” Zoghbi said.
Recently, in a separate study published in Nature, Zoghbi, Dr. Jianrong 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 where a specific region of the brain is stimulated with the aim of regulating abnormal activity and it is being used increasingly for many movement disorders.
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,” Zoghbi said. “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.”