Altered hippocampal synaptic plasticity in the FMR1 gene family knockout mouse models.
Fragile X syndrome (FXS) is the most common form of inherited mental retardation. The syndrome results from the absence of the fragile X mental retardation protein (FMRP), which is encoded by the fragile X mental retardation 1 (FMR1) gene. FMR1 and its two paralogs, fragile X-related genes 1 and 2 (FXR1 and -2), form the Fmr1 gene family. Here, we examined long-lasting synaptic plasticity in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice. We found that metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus was affected in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice at young ages (4-6 wk old). In addition, Fmr1/Fxr2 double knockout mice showed significant deficiencies relative to either Fmr1 or Fxr2 knockout mice in baseline synaptic transmission and short-term presynaptic plasticity, suggesting FMRP and FXR2P may contribute in a cooperative manner to pathways regulating presynaptic plasticity. However, compared with wild-type littermates, late-phase long-term potentiation (L-LTP) was unaltered in all knockout mice at 4-6 mo of age. Interestingly, although Fmr1/Fxr2 double knockout mice exhibited a more robust enhancement in mGluR-LTD compared with that in Fmr1 knockout mice, Fxr2 knockout mice exhibited reduced mGluR-LTD. Furthermore, unlike Fmr1 knockout mice, mGluR-LTD in Fxr2 knockout mice required new protein synthesis, whereas mGluR-LTD in Fmr1/Fxr2 double knockout mice was partially dependent on protein synthesis. These results indicated that both FMRP and FXR2P function in synaptic plasticity and that they likely operate in related but independent pathways.
Zhang
Jing
J
Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, TX 77030, USA.
Hou
Lingfei
L
Klann
Eric
E
Nelson
David L
DL
D000704:Analysis of Variance; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D001703:Biophysics; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics*; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology; D018408:Patch-Clamp Techniques; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology; D013569:Synapses / Q000235:genetics*
D000841:Anisomycin; D051860:Fragile X Messenger Ribonucleoprotein 1; D008734:Methoxyhydroxyphenylglycol; D011500:Protein Synthesis Inhibitors; D016601:RNA-Binding Proteins; D018094:Receptors, Metabotropic Glutamate; C512309:FXR2 protein, mouse; C497684:Fmr1 protein, mouse; C496283:Fxr1h protein, mouse; C104077:metabotropic glutamate receptor type 1; C010117:3,4-dihydroxyphenylglycol