Hongbing Wang, Ph.D., Principal Investigator
Michigan State University

FRAXA Awards:
  $45,000 in 2010

by Hongbing Wang, 4/2010

The mGluR theory of fragile X syndrome (FXS) emphasizes that overactivation of mGluR-mediated signaling may represent a major cause for FXS-associated symptoms. Although general inhibition of mGluR5 has shown promising therapeutic value, identification of specific downstream molecular targets will render more specific intervention. Several lines of evidence have shown that the level of basal cyclic AMP (cAMP) is lower in FXS patients and animal models, suggesting that cAMP may play a role in FXS etiology and may be a therapeutic target. Therefore, it is important to identify the linkage between mGluR and cAMP, as well as the approaches to manipulate basal cAMP level and achieve therapy.

The major enzymes that convert ATP to cAMP are adenylyl cyclases. We have identified a specific adenylyl cyclase (AC) whose activity is regulated by group I mGluR. Knockout mice for this AC showed significant less mGluR-mediated long-term depression (LTD) in vivo. The goal of this proposal is to examine the therapeutic value of this AC in Fmr1 KO mice. Double transgenic mice for Fmr1 and this AC will be examined for FXS-associated phenotypes such as mGluR-LTD, hyperactivity, and hyperarousal.

Although drugs that directly modulate the activity of this AC have not been identified, several available reagents may indirectly affect its activity. Once the therapeutic value of this AC is validated, these reagents could be applied as the next step for therapy.