title: Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse.
abstract: Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1 knockout (KO) mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC). To investigate the mechanisms for this, whole-cell voltage-clamp recordings of ASSN stimulation-evoked synaptic currents were made in APC of slices from adult Fmr1-KO and wild-type (WT) mice, using the competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CPP, to distinguish currents mediated by NMDA and AMPA receptors. NMDA/AMPA current ratios were lower in Fmr1-KO mice than in WT mice, at ages ranging from 3-18months. Since amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were no different in Fmr1-KO and WT mice at these ages, the results suggest that NMDA receptor-mediated currents are selectively reduced in Fmr1-KO mice. Analyses of voltage-dependence and decay kinetics of NMDA receptor-mediated currents did not reveal differences between Fmr1-KO and WT mice, suggesting that reduced NMDA currents in Fmr1-KO mice are due to fewer synaptic receptors rather than differences in receptor subunit composition. Reduced NMDA receptor signaling may help to explain the LTP deficit seen at APC ASSN synapses in Fmr1-KO mice at 6-18months of age, but does not explain normal LTP at these synapses in mice 3-6months old. Evoked currents and mEPSCs were also examined in senescent Fmr1-KO and WT mice at 24-28months of age. NMDA/AMPA ratios were similar in senescent WT and Fmr1-KO mice, due to a decrease in the ratio in the WT mice, without significant change in AMPA receptor-mediated mEPSCs.
authors: Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, USA.
authors: James
authors: J
authors: Gocel
authors: John
authors: J
authors: Larson
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001703:Biophysics; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000166:cytology* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D001640:Bicuculline; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D058787:GABA-A Receptor Antagonists; D016202:N-Methylaspartate; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C497684:Fmr1 protein, mouse; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid