Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome.
Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene (FMR1). The protein product of FMR1, fragile X mental retardation protein (FMRP) is an RNA-binding protein and may function as a translational suppressor. Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in hippocampal area CA1 is a form of synaptic plasticity that relies on dendritic protein synthesis. mGluR-LTD is enhanced in the mouse model of FXS, Fmr1 knockout (KO) mice, suggesting that FMRP negatively regulates translation of proteins required for LTD. Here we examine the synaptic and cellular mechanisms of mGluR-LTD in KO mice and find that mGluR-LTD no longer requires new protein synthesis, in contrast to wild-type (WT) mice. We further show that mGluR-LTD in KO and WT mice is associated with decreases in AMPA receptor (AMPAR) surface expression, indicating a similar postsynaptic expression mechanism. However, like LTD, mGluR-induced decreases in AMPAR surface expression in KO mice persist in protein synthesis inhibitors. These results are consistent with recent findings of elevated protein synthesis rates and synaptic protein levels in Fmr1 KO mice and suggest that these elevated levels of synaptic proteins are available to increase the persistence of LTD without de novo protein synthesis.
Nosyreva
Elena D
ED
Center for Basic Neuroscience, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9111, USA.
Huber
Kimberly M
KM
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D004195:Disease Models, Animal; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000378:metabolism* / Q000503:physiopathology*; D006624:Hippocampus / Q000473:pathology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D011500:Protein Synthesis Inhibitors; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
D015763:2-Amino-5-phosphonovalerate; D000841:Anisomycin; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D011500:Protein Synthesis Inhibitors; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C104077:metabotropic glutamate receptor type 1; C010117:3,4-dihydroxyphenylglycol