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Drug May Reverse Imbalance Linked to Autism Symptoms

Summary: According to researchers, a drug approved by the FDA may reverse some of the symptoms associated with Fragile X syndrome. The drug can reverse hyper-excitability that leads to sensory hypersensitivity.

Source: Northwestern Medical Center.

An FDA-approved drug can reverse an ionic imbalance in neurons that leads to hyper-excitability in mice modeling an autism-related genetic disorder, according to a Northwestern Medicine study published in Molecular Psychiatry.

These findings suggest that the sensory hypersensitivity experienced by patients with Fragile X syndrome, a syndromic autism, may be caused by elevated intracellular chloride in neurons during early development, according to Anis Contractor, PhD, professor of Physiology and senior author of the study.

“Some children with Fragile X syndrome or autism have changes in sensory processing, similar to the mouse model,” Contractor said. “The mouse models give us a window into the human disorder. Although mouse brain development is not a completely faithful model of humans, there certainly are parallels.”

While most genetic mutations that cause autism are very rare — and most cases of autism spectrum disorder are not linked to a genetic cause — children with Fragile X syndrome have a well-defined mutation in a gene on the X chromosome, so Fragile X syndrome is used as a laboratory model for certain aspects of autism, including sensory hypersensitivity.

“A lot of patients don’t like loud sounds or don’t like to be touched,” Contractor said. “When I talk to parents of children with Fragile X, some tell me these sensory issues lead to many other problems, because the kids are withdrawn or socially isolated.”

Prior studies in Contractor’s lab established the role of intracellular chloride in certain symptoms of Fragile X syndrome: While it is important for neurotransmitter signaling, high chloride concentration in neural cells can also cause abnormal excitation, shifting the timing of important developmental critical periods.

These critical periods are phases of early brain development where essential neural circuitry is formed; shifting them earlier or later affects how the brain is wired, as can be seen in the sensory cortex of mouse models. In normal mice, activity in a single whisker activates a single cluster of cells, relaying information about the force and direction in which the whisker was moved.

However, in mice with Fragile X syndrome, activity from a single whisker activates multiple clusters of cells, creating hyper-excitability.

“The activity bleeds to other clusters of cells, activating more cells than it normally would,” he said.

To investigate if this hyper-excitability could be reversed, Contractor and his colleagues treated mice for two weeks after birth with bumetanide, a drug originally used for hypertension.

“It’s actually not used very much anymore, because there are better drugs on the market now. But in addition to its effect on blood pressure it can affect neuronal chloride transporters and the influx of chloride into the cell,” Contractor said.

In mice with the Fragile X mutation, Contractor found it returned the concentration of intracellular chloride back to normal in neurons, shifting the critical periods back to their correct timing and leading to more typical synapse development.

autism sign

These critical periods are phases of early brain development where essential neural circuitry is formed; shifting them earlier or later affects how the brain is wired, as can be seen in the sensory cortex of mouse models. NeuroscienceNews.com image is in the public domain.

“We found that if we gave this drug early in development, it not only corrected the development of synapses during the early critical period, it also corrected the sensory problems we saw in adult mice,” Contractor said. “It is possible that correcting chloride or correcting neurotransmitter signaling in humans could also have the same effect.”

In fact, a high concentration of intracellular chloride could be associated with a variety of developmental disorders, not just Fragile X syndrome and autism, according to Contractor.

“We think it actually might be a more general mechanism, it’s been shown to play a role in Down syndrome and childhood epilepsies as well,” Contractor said. “People are interested in this chloride mechanism in a whole host of neurodevelopmental disorders.”

About this neuroscience research article

Contractor is also a professor in the Department of Neurobiology in the Weinberg College of Arts and Sciences. Qionger He, PhD, a former postdoctoral fellow in Contractor’s laboratory, was first author of the study. Feinberg co-authors include Jeffrey Savas, PhD, assistant professor in the Ken & Ruth Davee Department of Neurology and of Medicine and Pharmacology, Sam Smukowski, staff member in the Savas Laboratory and Jian Xu, PhD, research assistant professor of Physiology.

The authors also collaborated with Carlos Portera-Cailliau, MD, PhD, associate professor of Neurology at the University of Southern California-Los Angeles, and other members of his research group.

Source: Will Doss – Northwestern Medical Center
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice” by Qionger He, Erica D. Arroyo, Samuel N. Smukowski, Jian Xu, Claire Piochon, Jeffrey N. Savas, Carlos Portera-Cailliau & Anis Contractor in Molecular Psychiatry. Published April 27 2018.
doi:10.1038/s41380-018-0048-y

Cite This NeuroscienceNews.com Article
Northwestern Medical Center”Drug May Reverse Imbalance Linked to Autism Symptoms.” NeuroscienceNews. NeuroscienceNews, 8 May 2018.
<http://neurosciencenews.com/autism-drug-symptoms-8988/>.
Northwestern Medical Center(2018, May 8). Drug May Reverse Imbalance Linked to Autism Symptoms. NeuroscienceNews. Retrieved May 8, 2018 from http://neurosciencenews.com/autism-drug-symptoms-8988/
Northwestern Medical Center”Drug May Reverse Imbalance Linked to Autism Symptoms.” http://neurosciencenews.com/autism-drug-symptoms-8988/ (accessed May 8, 2018).

Abstract

Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice

Sensory perturbations in visual, auditory and tactile perception are core problems in fragile X syndrome (FXS). In the Fmr1 knockout mouse model of FXS, the maturation of synapses and circuits during critical period (CP) development in the somatosensory cortex is delayed, but it is unclear how this contributes to altered tactile sensory processing in the mature CNS. Here we demonstrate that inhibiting the juvenile chloride co-transporter NKCC1, which contributes to altered chloride homeostasis in developing cortical neurons of FXS mice, rectifies the chloride imbalance in layer IV somatosensory cortex neurons and corrects the development of thalamocortical excitatory synapses during the CP. Comparison of protein abundances demonstrated that NKCC1 inhibition during early development caused a broad remodeling of the proteome in the barrel cortex. In addition, the abnormally large size of whisker-evoked cortical maps in adult Fmr1 knockout mice was corrected by rectifying the chloride imbalance during the early CP. These data demonstrate that correcting the disrupted driving force through GABAA receptors during the CP in cortical neurons restores their synaptic development, has an unexpectedly large effect on differentially expressed proteins, and produces a long-lasting correction of somatosensory circuit function in FXS mice.

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