Synchronized oscillations and inhibitory interneurons have important and interconnected roles within cortical microcircuits. In particular, interneurons defined by the fast-spiking phenotype and expression of the calcium-binding protein parvalbumin1,2 have been suggested to be involved in gamma (30–80 Hz) oscillations3,4,5,6,7, which are hypothesized to enhance information processing8,9. However, because parvalbumin interneurons cannot be selectively controlled, definitive tests of their functional significance in gamma oscillations, and quantitative assessment of the impact of parvalbumin interneurons and gamma oscillations on cortical circuits, have been lacking despite potentially enormous significance (for example, abnormalities in parvalbumin interneurons may underlie altered gamma-frequency synchronization and cognition in schizophrenia10 and autism11). Here we use a panel of optogenetic technologies12,13,14 in mice to selectively modulate multiple distinct circuit elements in neocortex, alone or in combination. We find that inhibiting parvalbumin interneurons suppresses gamma oscillations in vivo, whereas driving these interneurons (even by means of non-rhythmic principal cell activity) is sufficient to generate emergent gamma-frequency rhythmicity. Moreover, gamma-frequency modulation of excitatory input in turn was found to enhance signal transmission in neocortex by reducing circuit noise and amplifying circuit signals, including inputs to parvalbumin interneurons. As demonstrated here, optogenetics opens the door to a new kind of informational analysis of brain function, permitting quantitative delineation of the functional significance of individual elements in the emergent operation and function of intact neural circuitry.
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We thank S. Arber for her gift of the PV::Cre mice, and we acknowledge the advice and suggestions of R. C. Malenka, J. Huguenard and S. Baccus on this work. All materials are freely distributed and supported by the Deisseroth laboratory (http://www.optogenetics.org). K.D. is supported by the President and Provost of Stanford University, BioX, Bioengineering, and by NIMH, NIDA, CIRM, NSF, and the Keck, McKnight and Coulter Foundations. F.Z. is supported by NINDS, and V.S.S. is supported by a T32 postdoctoral research training fellowship from NIMH.
This file contains Supplementary Methods, Supplementary References, Supplementary Tables 1-2 and Supplementary Figures 1-8 with Legends.
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NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity
Molecular Psychiatry (2019)