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

Biol Psychiatry. 2015 Mar 15;77(6):556-68. doi: 10.1016/j.biopsych.2014.06.026. Epub 2014 Jul 18.


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.

Keywords: GIRK; Gamma frequency; Hyperexcitability; NMDAR1; Pyramidal neurons; Schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Beta Rhythm / physiology
  • Brain / physiology*
  • Cholecystokinin / metabolism
  • Evoked Potentials, Auditory
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • Gamma Rhythm / physiology
  • Glutamate Decarboxylase / metabolism
  • Memory, Short-Term / physiology
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nesting Behavior / physiology
  • Neural Pathways / physiology
  • Parvalbumins / metabolism
  • Prosencephalon / physiology
  • Pyramidal Cells / physiology*
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Social Behavior
  • Somatostatin / metabolism
  • Spatial Memory / physiology
  • Theta Rhythm / physiology


  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Gprin1 protein, mouse
  • Kcnj6 protein, mouse
  • Nerve Tissue Proteins
  • Parvalbumins
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Somatostatin
  • Cholecystokinin
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1