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.
|Number of pages||13|
|State||Published - Mar 15 2015|
Bibliographical noteFunding Information:
This work was supported by R01MH075916 (C-GH), 5R01DA023210-02 (SJS) , K01DA031747 (PIO), P50MH096891 (REG), and T32MH019112 (REG), as well as developmental funds from the University of Pennsylvania (SJS) . CRJ is currently affiliated with the University Clinic Balgrist, Zurich, Switzerland. SM is currently affiliated with The University of Tokyo Faculty of Medicine, Tokyo, Japan.
© 2015 Society of Biological Psychiatry.
- Gamma frequency
- Pyramidal neurons
ASJC Scopus subject areas
- Biological Psychiatry