Fragile X Research Tackles High Anxiety – Peter Vanderklish

It’s often said love makes the world go ’round.

For families of children with Fragile X, their worlds often evolve around anxiety.

Yes, we all know the signs of Fragile X anxiety: Ears begin turning red followed by incessant pacing, heavy breathing, stiffening body, flapping, jumping, avoidance or yelling. Sometimes, it’s the more severe screaming, pinching, scratching, biting and general tearing things up or, worse, the nuclear meltdown.

Peter Vanderklish, PhD, associate professor, Cell and Molecular Biology, The Scripps Research Institute, knows the signs all too well. He believes anxiety is among the most highly debilitating aspects of Fragile X.

Thanks to a grant from FRAXA, Vanderklish is studying why people with Fragile X suffer from such severe, persistent and largely intractable anxiety. His goal is to translate what he finds into therapies tailored to Fragile X by targeting anxiety as a core symptom. An additional goal is to treat other emotional symptoms stemming from anxiety, including reducing social aversion and improving cognition. There is also the possibility that alleviating anxiety may lead to cognitive improvement.

Dr. Vanderklish and his collaborator at Scripps, Dr. Walter Francesconi, have been taking a new look at the neural origins of anxiety in Fragile X. “One of the most exciting aspects of our current work is the synaptic and neural changes we see in the BNST (bed nucleus of the stria terminalis) of fmr1 knockout mice, which in principle should predispose to chronic anxiety” said Vanderklish, who has been awarded $415,000 in FRAXA funding since 2004. “This maps quite nicely to recent work we conducted, which showed high local changes in enzymes in these pathways. So, our new data and hypotheses — which were derived from a systems neurobiology view of chronic anxiety — find support in the results of a large, unbiased molecular screen for synaptic protein changes in Fragile X.”

Vanderklish believes his biggest potential research benefit will be to improve the day-to-day quality of life for those with Fragile X and their families by reducing social anxiety.

“We all know how disruptive even transient anxiety can be,” said Vanderklish, who earned a PhD. in Neurobiology, University of California, Irvine, in 1997. “So, when you consider anxiety in Fragile X is multiform, chronic, intense and largely intractable, you realize it must be a huge disruption to their well-being.”

Parent surveys confirm this, Vanderklish said.

“Many rank anxiety as the most disruptive and costly symptom of Fragile X,” he said. “We are currently trying to improve a social anxiety paradigm in mice to provide a better test of the anxiolytic effects of drugs that correct synaptic and neural imbalances in the BNST.”

Vanderklish said he is “very grateful” to FRAXA for supporting his project.

“Working on Fragile X impacts me in several ways,” he said. “On a scientific level, I have the opportunity to be part of a field that draws from all areas of neuroscience — one that is evolved in a rapid and meaningful way by a committed group of parents, scientists, clinicians and others. There’s a real chance here to translate basic research into effective mechanism-based therapies. I find the devotion and commitment shown by FRAXA to be inspirational.”

Vanderklish remains optimistic that viable therapies for Fragile X will emerge from the current set of approaches being advanced by the field.

“Recent efforts that focus more specifically on core symptoms of Fragile X,” he said, “such as sensory hypersensitivity and anxiety, may play a role in so many other symptoms, even cognitive impairment, and will be particularly fruitful.”