Researchers receive NIH grant to study mechanisms of auditory hypersensitivity in fragile X syndrome

UC Riverside researchers embark on 5-year project funded by the National Institutes of Health

Fragile X syndrome (FXS) is a genetic disorder in humans that causes social impairments and repetitive behaviors, and other behaviors on the autistic spectrum, as well as cognitive deficits. It is the most common inherited cause of intellectual disability and the most common cause of autism.

One aspect of FXS worthy of more research is auditory hypersensitivity – an increased sensitivity to sound through a negative emotional response, resulting in behaviors such as closing the ears with the hands or running away from the sound source. People with FXS also are slow to adapt to constant repetitious sounds in our environment. These hypersensitivity deficits may lead to higher-level auditory deficits such as those involving language.

The University of California, Riverside has received a grant from the National Institutes of Health (NIH) to study the mechanisms of auditory hypersensitivity in FXS from molecules to circuits to therapies.

The five-year $8.7 million grant is awarded to UC Riverside and the University of Texas Southwestern (UTSW) Medical Center, Dallas. UCR will receive approximately $2.7 million of the grant over five years.

NIH recently awarded a total of $35 million to three different centers in the United States to study FXS, allowing the establishment of "Centers for Collaborative Research in FXS." The UTSW-UCR collaboration is one of the three centers.

The UCR team is being led by Khaleel Razak, an associate professor of psychology; and the School of Medicine's Iryna Ethell, a professor of biomedical sciences, and Devin Binder, an associate professor of biomedical sciences. The team came together for the project through a collaborative seed grant provided by the Office of Research and Economic Development at UCR and a pilot grant from the FRAXA Research Foundation.

FXS affects 1 in 4000 boys and is half as prevalent in girls. Symptoms include social and communication deficits, seizures, delayed language development and sensory hypersensitivity. Despite the prevalence of FXS and the known genetic cause, a cure is yet to be discovered.

"Two recent clinical trials of drugs were suspended because the drugs performed similar to the placebo on outcome measures," Razak said. "There is, therefore, an urgent need to develop new therapeutic targets and appropriate biomarkers and outcome measures in which the underlying neural mechanism is known at multiple levels of analyses."

The UCR team will study a mouse model of FXS to understand the neural mechanisms of auditory deficits. Razak, an auditory neurophysiologist, will examine the development of response selectivity in cortical neurons. Ethell, a molecular neurobiologist, will focus on the structural development of neurons in the auditory cortex and targeting an enzyme for drug development. Binder, a neurosurgeon and expert on seizures, will focus on identifying auditory physiological biomarkers. The UTSW team will take some of these discoveries, expected to be broadly applicable for autism research, from the bench to the bedside by testing outcome measures in FXS patients.

"The typical focus in pre-clinical translational research such as ours is to identify key molecular pathways in a rodent model of the disease and to test the efficacy of such molecules on various cognitive behaviors," Ethell said. "The underlying assumption is that the mouse cognitive behaviors may utilize similar neural circuits as humans. However, the neural circuits of complex cognitive behaviors are difficult to tease apart and very little information is available on the effects of the molecular manipulation on neural circuit function."

Binder explained that basic sensory behaviors and responses are more tractable from a neural circuit perspective and are likely to be relatively more conserved across species.

"This was the main justification for forming the UCR/UTSW collaboration to study auditory processing and behaviors," he said. "Humans with FXS and the mouse model exhibit similar auditory deficits. For low-level auditory cortical processing, the underlying mechanisms will be similar."

Studies resulting from the work done by the UCR team will identify these underlying mechanisms, making it possible for drug development to take an integrated 'molecules-circuits-behavior' approach.

"It is important to stress that drugs developed for FXS will also benefit children with autism," Ethell said. "Studies such as ours fit well with the White House's recent BRAIN Initiative."

Source: University of California - Riverside


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