Mark Bear, PhD, Principal Investigator
Asha Bhakar, PhD, Postdoctoral Fellow (2009)
Dilja Krueger, PhD, Postdoctoral Fellow (2008-9)
Emily Osterweil, PhD, Postdoctoral Fellow (2006-8)
Massachusetts Institute of Technology (MIT)

The mGluR Theory was proposed by Dr. Bear, Dr. Kimberly Huber, and colleagues in the year 2000. The theory states that symptoms of Fragile X arise from overactivity of one pathway that is critical for brain function: the mGluR pathway. Drugs which dampen this pathway (mGluR5 antagonists) might treat Fragile X.

by Asha Bhakar, PhD, Postdoctoral Fellow, 5/2009

The majority of Fragile X individuals suffer from mental disabilities, suggesting that cognitive impairment is a central problem in Fragile X Syndrome (FXS). The mechanistic basis for cognitive impairment, however, remains unclear, and currently there is no known cure. Hope for a treatment is plausible though, since patient neurons do not appear damaged or destroyed. In fact, the neuronal circuitry that is largely formed before birth is grossly normal in Fragile X patients, and it is the fine synaptic connections, the structural sites for neurotransmission between neurons, that appear disrupted in FXS. These synaptic connections, and their modification by experience, are thought to underlie the fundamental mechanisms of cognitive functioning. Given that synaptic connections are highly plastic after birth and remain so in Fragile X, we believe that drugs that can correct the disease will work by influencing the components that regulate synaptic connectivity. In this research project, we will begin to test this hypothesis by developing a high-throughput assay that specifically studies the synaptic connectivity defects underlying FXS and is suitable for drug discovery.

One type of high-throughput assay, High-Content Screening (HCS), is capable of reporting on subtle features of cultured neurons including changes in synaptic connectivity. In this research project, we will use HCS to develop an assay sensitive to the effect of the FXS genotype (validation step 1), and then to test the ability of an mGluR5 antagonist in restoring the effects of the FXS genotype to normal in this assay (validation step 2). Once validated, this HCS assay will be used to screen existing Food and Drug Administration (FDA)-approved compounds for effectiveness in Fragile X.

Results from this project would establish the first cell-based morphological and functional tool directly relevant for treating the neuronal deficits underlying cognitive impairment in FXS and would bridge the gap between basic synaptic/cellular biology and preclinical animal model testing. Moreover, since several collections of FDA approved drugs have proven to be rich sources of undiscovered bioactivity and therapeutic potential, drugs discovered to treat mental impairments in this HCS assay may have immediate application to treatment of FXS and may also help treat autism

by Mark Bear, 6/2003

We hypothesize that Fragile X syndrome is a consequence of exaggerated responses to synaptic activation of the group 1 mGluRs that are coupled to local protein synthesis. One consequence of this defect is that some AMPA receptors are pulled away from the surface of the neuron, leaving fewer AMPA receptors at the cell surface to perform their normal function. This hypothesis fits neatly with the studies of Dr. Berry-Kravis and Dr. Lauterborn, because Ampakine drugs work by enhancing the function of the fewer AMPA receptors still left. Another consequence of excessive mGluR function is initiation of epileptiform activity, which may explain why many children with Fragile X have seizures.

The goal of this project is to determine if the malfunction in the mGluR pathway causes the delayed development of synapses, using the Fragile X mouse model. If so, we will investigate whether mGluR antagonists, like MPEP, will correct this delayed development. Thus the overall goal of this study is to further investigate mGluR antagonists as potential treatments for Fragile X.