Eric Klann, Lingfei Hou

Eric Klann, PhD
Principal Investigator
Lingfei Hou, Ph.D
Postdoctoral Fellow
Baylor College of Medicine

FRAXA Awards:
  $60,000 in January 2006
  $60,000 in 2005
  $57,000 in 2004
  $40,000 in 2003

Dr. Klann, who has been funded by FRAXA from 2003 to the present, collaborates with several other Fragile X investigators at Baylor University, the site of one of the federally-funded Fragile X Research Centers created under the Children's Health Act of 2000.

Studies have shown that FMRP is a mRNA binding protein, and that one of its "targets" is the mRNA for a protein called MAP1b. The fmr1 knockout mouse, which lacks FMRP, has much more MAP1b in neurons than control animals. The KO mouse also shows much more Long Term Depression (LTD) in response to stimulation of specific glutamate receptors (mGluRs). This suggests that mGluR-LTD may be enhanced in Fmr1 knockout mice because of an increase in the translation of specific mRNAs, such as MAP1b. Our studies are designed to investigate this possibility.

Our current experiments build upon our previous studies funded by FRAXA. We have identified several proteins whose levels are rapidly increased during mGluR-LTD in wildtype mice. In each case, the baseline levels of these proteins are increased in the brain of KO mice, as compared to their wildtype littermates. Furthermore, we found that mGluR-LTD in Fmr1 knockout mice did not result in an increase in the levels of these proteins. One of these proteins is MAP1b. Our current studies focus on mGluR5-dependent regulation of MAP1b during mGluR-LTD in Fmr1 knockout mice. We will use mGluR5 and MAP1b knockout mice to determine whether the enhanced mGluR-LTD in Fmr1 knockout mice can be reversed. We believe that these studies will provide important information concerning the defective synaptic plasticity observed in mouse models of fragile X syndrome - information that could be relevant for treatment of patients with fragile X.

Previous studies indicate that FMRP binds to certain mRNAs and may regulate the translation of these mRNAs into proteins. As explained above, other studies show that mGluR-LTD is enhanced in mice that lack FMRP. Taken together, these two findings suggest the intriguing possibility that mGluRLTD may be enhanced in Fragile X mice because of an increase in the translation of specific mRNAs. We are investigating this possibility.

We have found that several signaling pathways couple mGluRs to the protein translation machinery during mGluR-LTD. These pathways point to candidate mRNAs that may be rapidly translated after the induction of LTD. We have observed that rapid translation of several mRNAs occurs during LTD in normal mice, and that, in contrast, translation of these mRNAs is altered in Fragile X mice. In complementary studies, we have begun to study mGluRLTD in mice that overexpress human FMRP (YAC FMR1 transgenic mice) to determine whether there are differences in LTD-induced mRNA translation between wildtype mice and YAC FMR1 transgenic mice.

We believe that identifying mRNAs translated in response to mGluR activation, and finding out whether their translation is altered during LTD in FMR1 knockout mice and/or YAC FMR1 transgenic mice, will be helpful in designing therapeutic agents for the treatment of patients with Fragile X.