Whisker stimulation-dependent translation of FMRP in the barrel cortex requires activation of type I metabotropic glutamate receptors.
Fragile X syndrome is a common inherited cause of mental retardation that results from the absence of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein thought to regulate translation of bound mRNAs, including its own. Previous studies in our laboratory have shown that FMRP expression increases in the barrel cortex of the rat after unilateral whisker stimulation, a model of experience dependent plasticity. This increase in protein is restricted to sub-cellular fractions enriched for synaptic or poly-ribosomal complexes. Here, we demonstrate that these increases are not accompanied by a change in FMR-1 mRNA levels and that they are blocked by the protein synthesis inhibitor cycloheximide in a dose dependent manner. Whisker stimulation dependent expression of FMRP is also abolished by pharmacological blockade of either NMDA receptors (MK-801, 0.25 mg/kg) or type I metabotropic glutamate receptors (AIDA, 5 mg/kg). In primary cortical neurons, activation of type I mGluRs leads to an increase in FMRP expression that is not effected by blockade of NMDA receptors. Taken together, these studies show that experience regulates FMRP production in vivo at the level of translation and supports a role for FMRP in metabotropic glutamate receptor mediated synaptic plasticity.
Todd
Peter K
PK
Department of Pathology, University of Wisconsin at Madison, Madison, WI, USA.
Malter
James S
JS
Mack
Kenneth J
KJ
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010812:Physical Stimulation; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013003:Somatosensory Cortex / Q000187:drug effects / Q000378:metabolism*; D014738:Vibrissae / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C497685:Fmr1 protein, rat