Robert Wong, PhD—State University of New York
Bi-Directional Regulation of Group I mGluR Responses by NMDA Receptors in FXS

Robert Wong, PhD, Principal Investigator (2004 to Present)
Wangfa Zhao, PhD, Postdoctoral Fellow (2013)

FRAXA Awards:

$45,000 in 2013
$45,000 in 2006
$46,000 in 2004


Dr. Wong began his Fragile X studies after our 2003 Fragile X Banbury meeting. He is investigating how seizures are generated in Fragile X neurons. More generally, he is looking at how synapses are modified to enable learning and memory and how this process is impaired in Fragile X.
mGluR Responses by NMDA Receptors in FXS

by Robert Wong, PhD, 5/20/2013

Abnormal increases in sensitivity of a type of glutamate receptor (group I metabotropic glutamate receptor or group I mGluR) cause brain malfunction, including epilepsy, in fragile X syndrome (FXS). This proposal will examine a newly uncovered regulation of this increased group I mGluR sensitivity by a second type of glutamate receptor, the NMDA receptor. By looking at audiogenic seizure in FXS model mice, NMDA receptor blockers were found to robustly suppress FXS-related audiogenic seizure at the young developmental stage. In contrast, the same antagonists activated seizure activities, normally dormant, in adult FXS model mice and in a CGG premutation model mouse. The research will explore whether drugs targeting NMDA receptors can be used to combat FXS and related conditions.
2013-Project details: Bi-Directional Regulation of Group I mGluR Responses by NMDA Receptors in FXS

by Michael Tranfaglia, 4/1/2013

One overarching theory of fragile X and other autism spectrum disorders is that the balance between excitatory and inhibitory neurotransmission is shifted toward excess excitation, with too little inhibition. This explains the interest in studies of inhibitory function (usually mediated by the major inhibitory neurotransmitter GABA); it also explains why many basic and clinical researchers are interested in exploring the therapeutic potential of drugs which block certain aspects of excitatory transmission (mainly mediated by glutamate.) While enthusiasm remains high for the use of mGluR5 antagonists, other classes of drugs are being tested which block other glutamate receptors. One other class of receptor is NMDA, the single most common glutamate receptor in the brain. NMDA receptor antagonists are being tested in animal models of fragile X and autism, and some available drugs with weak NMDA antagonism (such as acamprosate and memantine) are in human clinical trials. This project will investigate a curious paradox: NMDA antagonists given to young fragile X knockout mice seem to have a therapeutic effect similar to mGluR5 antagonists, blocking seizures and other aspects of fragile X. However, the same drugs given later in life have exactly the opposite effect, aggravating those same symptoms. These results suggest a strong interaction between NMDA and mGluRs which is developmentally regulated, and this group will investigate this connection, which has significant treatment implications.
Metabotropic Glutamate Receptor Function in Fragile X

by Robert Wong, 3/1/2004

 

We are studying the processes that cause the normal brain to become epileptic. There may be multiple mechanisms involved. We study seizures triggered by the activation of one kind of neuronal receptor, metabotropic glutamate receptors (mGluRs), in hippocampal neurons of mice. When hippocampal neurons are exposed to chemicals which stimulate only group 1 mGluRs, the neurons fire epileptiform discharges (which trigger seizures). We and others have shown that this occurs only if new proteins are being synthesized.

Our results show that intense stimulation of the glutamate synapses cannot elicit the group 1 mGluR-mediated epileptogenesis in normal mice. Apparently, neurons of normal mice have a mechanism to protect them from seizures. In contrast, using tissue from Fragile X knockout mice, this same stimulation easily and consistently elicited robust seizure activity.

We are testing the theory that in normal mice, the protein FMRP suppresses group 1 mGluR-dependent epileptogenesis by suppressing the translation of one or more proteins which are involved in triggering seizures. Our experiments will evaluate whether the function of group 1 mGluRs is exaggerated in neurons in the cortex of Fragile X knockout mouse. We plan to extend our studies to evaluate whether abnormalities in mGluR function can also affect other basic brain functions involved in learning and memory.