With a 2017 grant from FRAXA Research Foundation of $90,000, Dr. Andreas Frick’s team at Neurocentre Magendie, in France, will test non-invasive imaging using magnetic resonance imaging (MRI) as a potential biomarker for future fragile X syndrome clinical trials.
There is an urgent need for improved outcome measures for fragile X clinical trials. Behavioral ratings can be subjective and hard to quantify, so we need tests that can evaluate a potential treatment’s biological effects in an objective and easily measurable way. Really good measures might be used for stratifying patients likely to respond to a given treatment. Ideally, they should work in both mouse models and human patients.
Dr. Frick’s team will explore non-invasive imaging approaches using magnetic resonance imaging (MRI). They will first measure defects in the structural and functional connectivity of key brain networks in fragile X mice. With these mice, they will test the therapeutic potential of three promising molecules targeting known aspects of fragile X physiopathology.
If they are able to correct connectivity defects by chronic pharmacological intervention, they will evaluate changes in behaviors following treatment to correlate behavioral parameters with their connectivity measures.
If this project is successful, we will have objective outcome measures to evaluate new treatments, both in mice bred to mimic fragile X and in human patients.
Kamila Castro Grokoski
Inherited Channelopathies in Cortical Circuits of Fmr1 KO Mice
$90,000 over 2 Years
with Yu Zhang, PhD; FRAXA Postdoctoral Fellow
Many other proteins are misregulated as a result of the absence of FMRP. It is known that many ion channels, the pores in the cell membrane which allow neurons to conduct electrical impulses, have altered levels in fragile X. This state is sometime called a “channelopathy” in the pharma world. This group is studying the effect of specific alterations in ion channels, and potential therapeutic effects of drugs which open and close these channels.
The mammalian neocortex is central for processes as diverse as sensory information processing, perception or control of motor activity, and cortical defects have devastating neurological and psychiatric consequences. In humans, the consequences of Fragile X Syndrome include hypersensitivity to sensory stimuli, autistic behavior, seizures, and learning and memory deficits.
Ion channel defects (channelopathies) are increasingly being recognized as a crucial feature of many central nervous system disorders, but have—with the exception of few studies—not been implicated in Fragile X Syndrome. The mRNAs of several ion channel subunits are regulated by FMRP. Ion channels strongly determine the properties of dendrites, the ‘brains’ of neurons regulating information processing, information storage, and the action potential output of these neurons and thereby of the entire neuronal circuit. Thus, any change in the expression pattern and properties of ion channels will alter these parameters.
Data from our own lab indeed strongly suggest significant changes in the dendritic function of neocortical neurons of Fmr1KO mice. Based on these data and other studies we therefore hypothesize that alterations in ion channel function are a crucial feature of Fragile X Syndrome, and that these alterations might provide “drugable” targets for new therapeutic strategies treating Fragile X Syndrome and Autism Spectrum Disorders. Strong focus of our project will be given at aiming to rescue dendritic information processing in vitro and in vivo using existing and novel drugs. The concept of ‘channelopathy’ promises new avenues for therapeutic treatment and a better understanding of Fragile X Syndrome and Autism Spectrum Disorders in general.