Abnormal increases in sensitivity of a type of glutamate receptor (group I mGluR) cause brain malfunction, including epilepsy, in Fragile X syndrome (FXS). We are examining 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 seizures in FXS model mice, NMDA receptor blockers were found to robustly suppress these seizures 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. We will explore whether drugs targeting NMDA receptors can be used to combat FXS and related conditions.

Several drugs with NMDA receptor antagonist profiles, including memantine, acamprosate and dextromethorphan, have been studied in FXS and autism research. One of these drugs, acamprosate, is well into a clinical trial for Fragile X. Our results to date show that antagonists against NR2B, a subunit of NMDA receptor, have suppressive effects on group I mGluR action and is thus potently anticonvulsive in Fragile X mice. In contrast, antagonists against NMDAR subunits other than NR2B, potentiate group I mGluR-mediated responses. Interestingly, memantine exhibits properties typical of NR2B antagonists and is effective against group I mGluR responses including seizure discharges in FXS model mice.

The overall hypothesis is that antagonists against NMDA receptor subunit NR2B elicit clinically beneficial action via regulation of group I mGluR actions without activating deleterious side effects caused by broad spectrum NMDAR blockers.