|Final Report - Manipulating basal and mGluR-stimulated cAMP level in FXS model mice
by Hongbing Wang, 8/29/2012
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.
Recently, 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. To test the therapeutic effects by genetic deletion of this AC, we made double transgenic mouse and examined hyperactivity, hyperarousal, and repetitive behaviors. Our preliminary results showed that, compared to Fmr1 knockout (KO) mice, double KO animals lacking both Fmr1 and AC displayed attenuation of these phenotypes. At the CA1 synapses, double KO mice did not show significant mGluR-LTD. We plan to further determine whether deletion of this AC also corrects cognitive impairments and abnormal neuronal morphology.
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.