title: Synaptic and extrasynaptic plasticity in glutamatergic circuits involving dentate granule cells following chronic N-methyl-D-aspartate receptor inhibition.
abstract: Chronic global N-methyl-d-aspartate receptor (NMDAR) blockade leads to changes in glutamatergic transmission. The impact of more subunit-selective NMDAR inhibition on glutamatergic circuits remains incomplete. To this end, organotypic hippocampal slice cultures were treated for 17-21 days with the high-affinity competitive antagonist d-aminophosphonovaleric acid (d-APV), the allosteric GluN2B-selective antagonist Ro25-6981, or the newer competitive GluN2A-preferring antagonist NVP-AAM077. Electrophysiological recordings from dentate granule cells revealed that chronic d-APV treatment increased, whereas chronic Ro25-6981 reduced, epileptiform event-associated large-amplitude spontaneous excitatory postsynaptic currents (sEPSC) compared with all other treatment groups, consistent with opposite effects on glutamatergic networks. Presynaptically, chronic d-APV or Ro25-6981 increased small-amplitude sEPSCs and AMPA/kainate receptor-mediated miniature EPSCs (mEPSCAMPAR) frequency. Chronic d-APV or NVP-AAM077, but not Ro25-6981, increased putative vGlut1-positive glutamatergic synapses. Postsynaptically, chronic d-APV dramatically increased mEPSCAMPAR and profoundly decreased NMDAR-mediated mEPSC (mEPSCNMDAR) measures, suggesting increased AMPAR/NMDAR ratio. Ro25-6981 decreased mEPSCAMPAR charge transfer and modestly decreased mEPSCNMDAR frequency and decay, suggesting downward scaling of AMPAR and NMDAR function without dramatically altering AMPAR/NMDAR ratio. Extrasynaptically, threo-β-benzyloxyaspartate-enhanced "tonic" NMDAR current amplitude and activated channel number estimates were significantly increased only by chronic Ro25-6981. For intrinsic excitability, action potential threshold was slightly more negative following chronic d-APV or NVP-AAM077. The predominant pro-excitatory effects of chronic d-APV are consistent with increased glutamatergic transmission and network excitability. The minor effects of chronic NVP-AAM077 on action potential threshold and synapse number are consistent with minimal effects on circuit function. The chronic Ro25-6981-induced downward scaling of synaptic AMPAR and NMDAR function is consistent with decreased postsynaptic glutamate receptors and reduced network excitability.
authors.affiliation: Graduate Program in Neuroscience, Uniformed Services University School of Medicine, Bethesda, Maryland 20814-4799, USA.
authors.forename: Shuijin
authors.initials: S
authors.lastname: He
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Shao
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Bausch
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D055369:Miniature Postsynaptic Potentials; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010636:Phenols; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: C498554:5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione; D018691:Excitatory Amino Acid Antagonists; D010636:Phenols; D010880:Piperidines; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D050598:Vesicular Glutamate Transport Protein 1; D015763:2-Amino-5-phosphonovalerate