FRAXA Research Foundation - finding a cure for Fragile X

Suzanne Zukin, PhD
Principal Investigator
Sho Fujisawa, PhD
Postdoctoral Fellow
Albert Einstein College of Medicine

FRAXA Awards:
  $60,000 in 2008
  $65,000 in 2007
  $40,000 in 2006

Activity-Dependent Trafficking of AMPA Receptor mRNAs in Dendrites

by Michael Tranfaglia, FRAXA, 4/2007

The long-term goal of this research is to elucidate the molecular mechanisms underlying regulated AMPA recptor trafficking in dendrites under physiological and pathological (fragile X) conditions. Our hypothesis is that cognitive impairments in Fragile X result from dysregulation of messenger RNA localization and local protein synthesis. We will use a combination of molecular, biochemical and imaging techniques to examine activity-dependent and developmental regulation of mGluR-dependent trafficking of AMPA receptor mRNAs in dendrites and targeting to synaptic sites in neurons from wild-type and Fmr1 KO mice. An important goal is to identify possible alterations in AMPAR mRNA trafficking in the fragile X mouse. In addition, we will identify signaling pathways involved in regulation of dendritic targeting of AMPAR mRNAs and local protein synthesis and examine their possible dysregulation in KO mice. A focus will be on the PI3-kinase, CREB and mTOR signaling cascades known to be downstream of group I mGluR activation and important to local protein synthesis. Understanding the mechanisms underlying abnrmalities of mGluR-dependent synaptic plasticity could help in the development of novel therapeutic strategies to ameliorate cognitive deficits in Fragile X Syndrome.

Activity Bidirectionally Regulates AMPA Receptor mRNA Abundance in Dendrites of Hippocampal Neurons

Yukihiro Takayasu, MD, PhD
FRAXA Postdoctoral Fellowship in 2006

by Suzanne Zukin, 3/2006

Regulated mRNA trafficking and local protein synthesis play central roles in synaptic remodeling and plasticity. By spatially restricting gene expression within microdomains, local protein synthesis endows neurons with the capacity to autonomously regulate their structure and function.

We recently found that AMPAR mRNAs are targeted to synapses and that mGluR activation promotes targeting of AMPAR mRNAs to synaptic sites. The goal of this project is to determine if dysregulation of mRNA localization and local protein synthesis impairs synaptic transmission, using the Fragile X mouse model. We will use a combination of molecular biological and live-cell imaging techniques to examine precisely how stimulating mGluRs affects AMPA receptor mRNA targeting to synaptic sites and local synthesis of AMPA receptor protein in dendrites.

Understanding the mechanisms underlying dysregulation of mGluR-dependent synaptic plasticity could help in the development of novel therapeutic strategies to ameliorate cognitive deficits in Fragile X Syndrome.