Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability

Valerie M. Tatard-Leitman, Catherine R. Jutzeler, Jimmy Suh, John A. Saunders, Eddie N. Billingslea, Susumu Morita, Rachel White, Robert E. Featherstone, Rabindranath Ray, Pavel I. Ortinski, Anamika Banerjee, Michael J. Gandal, Robert Lin, Anamaria Alexandrescu, Yuling Liang, Raquel E. Gur, Karin E. Borgmann-Winter, Gregory C. Carlson, Chang Gyu Hahn, Steven J. Siegel

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

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.

Original languageEnglish
Pages (from-to)556-568
Number of pages13
JournalBiological Psychiatry
Volume77
Issue number6
DOIs
StatePublished - Mar 15 2015

Bibliographical note

Publisher Copyright:
© 2015 Society of Biological Psychiatry.

Keywords

  • GIRK
  • Gamma frequency
  • Hyperexcitability
  • NMDAR1
  • Pyramidal neurons
  • Schizophrenia

ASJC Scopus subject areas

  • Biological Psychiatry

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