Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors.
Fragile X syndrome (FXS), a common inherited form of mental retardation, is caused by the functional absence of the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates the translation of specific mRNAs at synapses. Altered synaptic plasticity has been described in a mouse FXS model. However, the mechanism by which the loss of FMRP alters synaptic function, and subsequently causes the mental impairment, is unknown. Here, in cultured hippocampal neurons, we used siRNAs against Fmr1 to demonstrate that a reduction of FMRP in dendrites leads to an increase in internalization of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit, GluR1, in dendrites. This abnormal AMPAR trafficking was caused by spontaneous action potential-driven network activity without synaptic stimulation by an exogenous agonist and was rescued by 2-methyl-6-phenylethynyl-pyridine (MPEP), an mGluR5-specific inverse agonist. Because AMPAR internalization depends on local protein synthesis after mGluR5 stimulation, FMRP, a negative regulator of translation, may be viewed as a counterbalancing signal, wherein the absence of FMRP leads to an apparent excess of mGluR5 signaling in dendrites. Because AMPAR trafficking is a driving process for synaptic plasticity underlying learning and memory, our data suggest that hypersensitive AMPAR internalization in response to excess mGluR signaling may represent a principal cellular defect in FXS, which may be corrected by using mGluR antagonists.
Nakamoto
Mika
M
Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Whitehead Biomedical Research Building, Atlanta, GA 30322, USA.
Nalavadi
Vijayalaxmi
V
Epstein
Michael P
MP
Narayanan
Usha
U
Bassell
Gary J
GJ
Warren
Stephen T
ST
D000818:Animals; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000502:physiology; D005600:Fragile X Syndrome / Q000235:genetics*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics*; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat