Peter K. Todd 1996-2004
Resident, Neurology
U of Pennsylvania Hospital, Philadelphia, PA
University of California - San Diego 1994
Neuroscience PhD 2002
Kenneth J Mack, James S Malter
Activity dependent translation of the fragile X mental retardation protein and its mRNA targets
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Fragile X syndrome (FXS) is the most common known inherited cause of mental retardation. The syndrome results from the absence of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein thought to regulate the translation of target mRNAs, including its own transcript. To better understand the functions of FMRP in the nervous system, I have studied its activity dependent expression in two model systems: the whisker to barrel cortex pathway of the rat and primary cultures of cortical neurons. FMRP levels increase in the barrel cortex after unilateral whisker stimulation, a model of experience dependent plasticity. These changes occur in sub-cellular fractions enriched for synaptosomes or polyribosomal complexes and require new protein synthesis, but are not associated with changes in FMRI mRNA levels. In addition, these changes are blocked by pre-treatment with pharmacological antagonists to either type one metabotropic glutamate receptors (mGluRs) or NMDA receptors.
In primary cortical neurons, application of the type one mGluR specific agonist S-3, 5 hydrophenylglycine (DHPG) leads to a rapid (maximal by 20 minutes) and robust (250%) increase in FMRP expression that requires new protein synthesis but not transcription. These changes are specific to mGluR activation, as activation with KCL does not induce any changes in FMRP expression. I also demonstrate that the mRNA for PSD-95, a synaptic scaffolding protein required for cortical plasticity and learning, contains a highly conserved canonical binding site for FMRP within its 3’ UTR. PSD-95 protein is rapidly translated in response to DHPG and this mGluR dependent translation is absent in neurons derived from FMRP knockout mice, a model of FXS. Taken together, these studies implicate a failure of activity dependent translation in the pathogenesis of FXS and imply a role for FMRP in mGluR mediated plasticity.
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| Thesis Publications |
- Todd PK, Mack KJ, Malter JS. The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. Proc Natl Acad Sci USA 100:14374-14378, 2003.
- Todd PK, Malter JS, Mack KJ. Whisker stimulation-dependent translation of FMRP in the barrel cortex requires activation of type I metabotropic glutamate receptors. Brain Res Mol Brain Res 110:267-278, 2003.
- Todd PK, Malter JS. Fragile X mental retardation protein in plasticity and disease. J Neurosci Res 70:623-630, 2002.
- Todd PK, Mack KJ. Phosphorylation, CREB, and mental retardation. Pediatr Res 50:672, 2001.
- Todd PK, Mack KJ. Sensory stimulation increases cortical expression of the fragile X mental retardation protein in vivo. Mol Brain Res 80:17-25, 2000.
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