title: Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability.
abstract: BACKGROUND
  Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear.
  
  
  METHODS
  In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice.
  
  
  RESULTS
  The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability.
  
  
  CONCLUSIONS
  Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Tatard-Leitman
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Jutzeler
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Suh
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: John A
authors.initials: JA
authors.lastname: Saunders
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Eddie N
authors.initials: EN
authors.lastname: Billingslea
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Susumu
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Rachel
authors.initials: R
authors.lastname: White
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Featherstone
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Rabindranath
authors.initials: R
authors.lastname: Ray
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Ortinski
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Anamika
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gandal
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Robert
authors.initials: R
authors.lastname: Lin
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Anamaria
authors.initials: A
authors.lastname: Alexandrescu
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Borgmann-Winter
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Carlson
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Chang-Gyu
authors.initials: CG
authors.lastname: Hahn
authors.affiliation: Translational Neuroscience Program, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: siegels@upenn.edu.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Siegel
mesh_terms: D000818:Animals; D001611:Beta Rhythm / Q000502:physiology; D001921:Brain / Q000502:physiology*; D002766:Cholecystokinin / Q000378:metabolism; D005072:Evoked Potentials, Auditory; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D065818:Gamma Rhythm / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D008570:Memory, Short-Term / Q000502:physiology; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009425:Nesting Behavior / Q000502:physiology; D009434:Neural Pathways / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism; D016548:Prosencephalon / Q000502:physiology; D017966:Pyramidal Cells / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012919:Social Behavior; D013004:Somatostatin / Q000378:metabolism; D065852:Spatial Memory / Q000502:physiology; D013826:Theta Rhythm / Q000502:physiology
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C121673:Gprin1 protein, mouse; C497069:Kcnj6 protein, mouse; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013004:Somatostatin; D002766:Cholecystokinin; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: GIRK; Gamma frequency; Hyperexcitability; NMDAR1; Pyramidal neurons; Schizophrenia