Home LiteratureArticle Details
PMID: 21468034 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior.

Molecular psychiatry ·Vol. 17 ·No. 5 ·2012-05-00 ·Pages 537-48

Carlén M, Meletis K, Siegle JH, Cardin JA, Futai K, Vierling-Claassen D, Rühlmann C, Jones SR, Deisseroth K, Sheng M, Moore CI, Tsai LH

Abstract

Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors.

MeSH Terms
Animals Association Learning/drug effects,physiology Brain Waves/drug effects,physiology Conditioning, Psychological/drug effects,physiology Excitatory Postsynaptic Potentials/drug effects,physiology GABA Antagonists/pharmacology GABAergic Neurons/metabolism,physiology Interneurons/drug effects,physiology Male Maze Learning/drug effects,physiology Memory, Short-Term/drug effects,physiology Mice Mice, Transgenic Parvalbumins/metabolism Photic Stimulation/methods Picrotoxin/pharmacology Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors,genetics,physiology Sensory Gating/drug effects,physiology Stereotyped Behavior/drug effects,physiology
Chemicals
GABA Antagonists NR1 NMDA receptor Parvalbumins Receptors, N-Methyl-D-Aspartate Picrotoxin
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Carlén M
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA. [email protected]
Meletis K
Siegle J H
Cardin J A
Futai K
Vierling-Claassen D
Rühlmann C
Jones S R
Deisseroth K
Sheng M
Moore C I
Tsai L-H
References (66)
66 references, click to expand
  1. Impairment of early cortical processing in schizophrenia: an event-related potential confirmation study.
    Biol Psychiatry. 1993 Apr 1;33(7):513-9 PMID: 8513035
  2. First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients.
    Mol Psychiatry. 2006 Feb;11(2):118-9 PMID: 16189506
  3. The development of parvalbumin-immunoreactivity in the neocortex of the mouse.
    Brain Res Dev Brain Res. 1994 Sep 16;81(2):247-59 PMID: 7813046
  4. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia.
    Nat Med. 2006 Jul;12(7):824-8 PMID: 16767099
  5. Neuropsychological function in schizophrenia. Selective impairment in memory and learning.
    Arch Gen Psychiatry. 1991 Jul;48(7):618-24 PMID: 2069492
  6. Modeling GABA alterations in schizophrenia: a link between impaired inhibition and altered gamma and beta range auditory entrainment.
    J Neurophysiol. 2008 May;99(5):2656-71 PMID: 18287555
  7. A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity.
    Trends Neurosci. 1998 Jul;21(7):273-8 PMID: 9683315
  8. Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior.
    Neuron. 2007 Feb 15;53(4):591-604 PMID: 17296559
  9. Region-specific reduction in entorhinal gamma oscillations and parvalbumin-immunoreactive neurons in animal models of psychiatric illness.
    J Neurosci. 2006 Mar 8;26(10):2767-76 PMID: 16525056
  10. Transformations towards the normal distribution of broad band spectral parameters of the EEG.
    Electroencephalogr Clin Neurophysiol. 1982 Jan;53(1):119-24 PMID: 6173196
  11. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.
    Arch Gen Psychiatry. 1994 Mar;51(3):199-214 PMID: 8122957
  12. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons.
    J Neurosci. 2007 Oct 24;27(43):11496-500 PMID: 17959792
  13. Constitutively active Rap2 transgenic mice display fewer dendritic spines, reduced extracellular signal-regulated kinase signaling, enhanced long-term depression, and impaired spatial learning and fear extinction.
    J Neurosci. 2008 Aug 13;28(33):8178-88 PMID: 18701680
  14. Working memory related gamma oscillations in schizophrenia patients.
    Int J Psychophysiol. 2007 Apr;64(1):39-45 PMID: 16962192
  15. Working memory in schizophrenia: a meta-analysis.
    Psychol Med. 2009 Jun;39(6):889-905 PMID: 18945379
  16. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks.
    Nat Rev Neurosci. 2007 Jan;8(1):45-56 PMID: 17180162
  17. Stimulus-dependent gamma (30-50 Hz) oscillations in simple and complex fast rhythmic bursting cells in primary visual cortex.
    J Neurosci. 2005 Jun 1;25(22):5339-50 PMID: 15930382
  18. Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms.
    Psychopharmacology (Berl). 2004 Nov;176(3-4):440-50 PMID: 15173930
  19. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes.
    Nat Neurosci. 2010 Jan;13(1):76-83 PMID: 19915563
  20. Gamma frequency-range abnormalities to auditory stimulation in schizophrenia.
    Arch Gen Psychiatry. 1999 Nov;56(11):1001-5 PMID: 10565499
  21. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia.
    Cell. 1999 Aug 20;98(4):427-36 PMID: 10481908
  22. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1.
    J Neurosci. 2008 Feb 13;28(7):1697-708 PMID: 18272690
  23. A role for inhibition in shaping the temporal flow of information in prefrontal cortex.
    Nat Neurosci. 2002 Feb;5(2):175-80 PMID: 11802172
  24. Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia.
    Cereb Cortex. 2009 Mar;19(3):612-8 PMID: 18632742
  25. Different capability of N-methyl-D-aspartate antagonists to elicit EEG and behavioural phencyclidine-like effects in rats.
    Psychopharmacology (Berl). 1992;109(3):277-82 PMID: 1365627
  26. Neural correlates of vibrissa resonance; band-pass and somatotopic representation of high-frequency stimuli.
    Neuron. 2004 May 13;42(3):451-63 PMID: 15134641
  27. Cellular bases of hippocampal EEG in the behaving rat.
    Brain Res. 1983 Oct;287(2):139-71 PMID: 6357356
  28. Relation between hippocampal gamma waves and behavioral disturbances induced by phencyclidine and methamphetamine.
    Behav Brain Res. 2000 Jun 15;111(1-2):1-11 PMID: 10840127
  29. Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia.
    Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19878-83 PMID: 17170134
  30. Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia.
    Ann N Y Acad Sci. 2003 Nov;1003:318-27 PMID: 14684455
  31. Cognition in mouse models of schizophrenia susceptibility genes.
    Schizophr Bull. 2010 Mar;36(2):289-300 PMID: 20026558
  32. NMDA receptor hypofunction leads to generalized and persistent aberrant gamma oscillations independent of hyperlocomotion and the state of consciousness.
    PLoS One. 2009 Aug 25;4(8):e6755 PMID: 19707548
  33. Efferent neurons and suspected interneurons in S-1 vibrissa cortex of the awake rabbit: receptive fields and axonal properties.
    J Neurophysiol. 1989 Jul;62(1):288-308 PMID: 2754479
  34. Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice.
    Hippocampus. 2010 Jun;20(6):724-44 PMID: 19655320
  35. A mechanism for generation of long-range synchronous fast oscillations in the cortex.
    Nature. 1996 Oct 17;383(6601):621-4 PMID: 8857537
  36. Recent advances in the phencyclidine model of schizophrenia.
    Am J Psychiatry. 1991 Oct;148(10):1301-8 PMID: 1654746
  37. Requirement for hippocampal CA3 NMDA receptors in associative memory recall.
    Science. 2002 Jul 12;297(5579):211-8 PMID: 12040087
  38. A somatotopic map of vibrissa motion direction within a barrel column.
    Nat Neurosci. 2006 Apr;9(4):543-51 PMID: 16547511
  39. Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia.
    Psychopharmacology (Berl). 2008 Oct;200(2):217-30 PMID: 18597079
  40. Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures.
    Schizophr Bull. 2007 Jan;33(1):69-94 PMID: 17135482
  41. Basket-like interneurones in layer II of the entorhinal cortex exhibit a powerful NMDA-mediated synaptic excitation.
    Neurosci Lett. 1993 Jan 4;149(1):35-9 PMID: 8469376
  42. Increased gamma- and decreased delta-oscillations in a mouse deficient for a potassium channel expressed in fast-spiking interneurons.
    J Neurophysiol. 1999 Oct;82(4):1855-64 PMID: 10515974
  43. N-methyl-d-aspartic acid receptor antagonist-induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia.
    Neuroscience. 2009 Jan 23;158(2):705-12 PMID: 19015010
  44. The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia.
    Biol Psychiatry. 1999 Sep 1;46(5):650-61 PMID: 10472417
  45. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory.
    Cell. 1996 Dec 27;87(7):1327-38 PMID: 8980238
  46. N-methyl d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant gamma oscillations in the rat neocortex.
    Biol Psychiatry. 2008 Apr 15;63(8):730-5 PMID: 18022604
  47. Word and tone working memory deficits in schizophrenia.
    Arch Gen Psychiatry. 1998 Dec;55(12):1093-6 PMID: 9862552
  48. The competitive NMDA antagonist AP5, but not the non-competitive antagonist MK801, induces a delay-related impairment in spatial working memory in rats.
    Exp Brain Res. 1991;85(2):349-58 PMID: 1680067
  49. A role for NMDA-receptor channels in working memory.
    Nat Neurosci. 1998 Aug;1(4):273-5 PMID: 10195158
  50. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus.
    BMC Dev Biol. 2001;1:4 PMID: 11299042
  51. Sensorimotor gating and schizophrenia. Human and animal model studies.
    Arch Gen Psychiatry. 1990 Feb;47(2):181-8 PMID: 2405807
  52. The gamma cycle.
    Trends Neurosci. 2007 Jul;30(7):309-16 PMID: 17555828
  53. Neuronal gamma-band synchronization as a fundamental process in cortical computation.
    Annu Rev Neurosci. 2009;32:209-24 PMID: 19400723
  54. Driving fast-spiking cells induces gamma rhythm and controls sensory responses.
    Nature. 2009 Jun 4;459(7247):663-7 PMID: 19396156
  55. The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia.
    Schizophr Bull. 2008 Sep;34(5):927-43 PMID: 18562344
  56. Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task.
    Psychopharmacology (Berl). 2001 Jan;153(3):353-64 PMID: 11271408
  57. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders.
    Nat Rev Neurosci. 2007 Jun;8(6):413-26 PMID: 17514195
  58. Cortical inhibitory neurons and schizophrenia.
    Nat Rev Neurosci. 2005 Apr;6(4):312-24 PMID: 15803162
  59. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5.
    Nature. 1986 Feb 27-Mar 5;319(6056):774-6 PMID: 2869411
  60. A developmental switch in the response of DRG neurons to ETS transcription factor signaling.
    PLoS Biol. 2005 May;3(5):e159 PMID: 15836427
  61. Hebbian LTP in feed-forward inhibitory interneurons and the temporal fidelity of input discrimination.
    Nat Neurosci. 2005 Jul;8(7):916-24 PMID: 15937481
  62. Differential modulation of CA1 and dentate gyrus interneurons during exploration of novel environments.
    J Neurophysiol. 2004 Feb;91(2):863-72 PMID: 14523073
  63. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.
    Nature. 2009 Jun 4;459(7247):698-702 PMID: 19396159
  64. Effects of NMDA receptor antagonists: implications for the pathophysiology of schizophrenia.
    Arch Gen Psychiatry. 2002 Jul;59(7):663-4 PMID: 12090822
  65. Neuregulin 1 and susceptibility to schizophrenia.
    Am J Hum Genet. 2002 Oct;71(4):877-92 PMID: 12145742
  66. Increased inhibitory input to CA1 pyramidal cells alters hippocampal gamma frequency oscillations in the MK-801 model of acute psychosis.
    Neurobiol Dis. 2007 Mar;25(3):545-52 PMID: 17169567
Article Info
Journal
Molecular psychiatry
Abbr.
Mol Psychiatry
ISSN
1476-5578
DOI
10.1038/mp.2011.31
Email
[email protected]
Published
2012-05-00
Epub
2011-00-05
Pages
537-48
Language
English
Region
England
NLM ID
9607835
PMCID
PMC3335079
Subset
IM
External Links
PubMed source DOI: 10.1038/mp.2011.31 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2