NMDA Receptor Hypofunction, Parvalbumin-Positive Neurons, and Cortical Gamma Oscillations in Schizophrenia
Open accessAbstract
Gamma oscillations appear to be dependent on inhibitory neurotransmission from parvalbumin (PV)-containing gamma-amino butyric acid neurons. Thus, the abnormalities in PV neurons found in schizophrenia may underlie the deficits of gamma-band synchrony in the illness. Because gamma-band synchrony is thought to be crucial for cognition, cognitive deficits in schizophrenia may reflect PV neuron dysfunction in cortical neural circuits. Interestingly, it has been suggested that PV alterations in schizophrenia are the consequence of a hypofunction of signaling through N-methyl-D-aspartate (NMDA) receptors (NMDARs). Here, we review recent findings that address the question of how NMDAR hypofunction might produce deficits of PV neuron-mediated inhibition in schizophrenia. We conclude that while dysregulation of NMDARs may play an important role in the pathophysiology of schizophrenia, additional research is required to determine the particular cell type(s) that mediate dysfunctional NMDAR signaling in the illness.
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In prefrontal cortex, NMDA-R impairments may lead to hypofunction of GABAergic PVBCs, disinhibition of pyramidal cells, and reduced prefrontal gamma activity.
“In the prefrontal cortex, NMDA-R impairments may lead to hypofunction of GABAergic PVBC’s, disinhibition of pyramidal cells, and reduced prefrontal gamma activity (Gonzalez-Burgos and Lewis, 2012)”
From The Computational Anatomy of Psychosis (2013) · cites this paper as Gonzalez-Burgos and Lewis, 2012
The section on NMDAR- and AMPA-mediated transmission reports pyramidal-cell disinhibition after NMDAR blockade in prefrontal cortex, but says it is unclear whether the affected GABA neurons are PVBCs. The section on gamma oscillations predicts that reducing NMDAR input to PVBCs would not reduce gamma power and reports evidence of increased gamma power instead. Thus, the paper argues against the claimed PVBC-to-reduced-gamma pathway. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredThe modification of the E/I balance within the PV-circuitry in PV-/- mice is reminiscent of the situation in schizophrenia, where NMDA receptor hypofunction leads to the reduction of GAD67 levels and thus GABA synthesis.
“The modification of the E/I balance within the PV-circuitry in PV-/- mice is reminiscent of the situation in schizophrenia, where NMDA receptor hypofunction leads to the reduction of glutamic acid decarboxylase 67 (GAD67) levels and thus GABA synthesis.”
AMPA-mediated EPSPs in PV interneurons have short time constants and are ideally suited to support gamma-band oscillations.
“AMPA-mediated EPSPs in PV interneurons have short time constants (fast kinetics) and are ideally suited to support gamma-band oscillations”
From Neuronal Dynamics and Neuropsychiatric Disorders: Toward a Translational Paradigm for Dysfunctional Large-Scale Networks (2012) · cites this paper as Gonzalez-Burgos and Lewis, 2012
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References 55 · Cited by 478
Research works printed but not linked: 2
- Lesh TA, Niendam TA, Minzenberg MJ, Carter CS. Cogni- tive control deficits in schizophrenia: mechanisms and mean- ing. Neuropsychopharmacology. 2011;36:316-338.
- Fuchs EC, Zivkovic AR, Cunningham MO, et al. Recruit- ment of parvalbumin-positive interneurons determines hippo- campal function and associated behavio. Neuron. 2007;53: 591-604.
- Authors
- Gonzalez-Burgos, G., & Lewis, D. A.
- Affiliations
- University of Pittsburgh (US)
- ORCID
- Lewis, D. A.
- Venue
- Schizophrenia Bulletin
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-02-21
- Volume
- 38
- Issue
- 5
- Pages
- 950-957
- ISSN
- 0586-7614 (ISSN-L)
- 1745-1701
- PMC
- PMC3446219
- OpenAlex
- W2115624750
- Cited by
- 478
- References
- 55
- Citations by year
- 2026: 23 · 2025: 32 · 2024: 27 · 2023: 27 · 2022: 30 · 2021: 37 · 2020: 38 · 2019: 24 · 2018: 40 · 2017: 40 · 2016: 36 · 2015: 52 · 2014: 38 · 2013: 25 · 2012: 9
- FWCI
- 5.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Schizophrenia Bulletin (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Pfizer
- SK Life Science
- National Institutes of Health (MH043784, MH084053)
- National Institute of Mental Health (P50MH084053, MH084053, R01MH043784, MH043784)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- schizophrenia, NMDA receptor hypofunction
- MeSH terms
- Animals, Awareness, Cerebral Cortex, Cholecystokinin, Cognition Disorders, Cortical Synchronization, Electroencephalography, Humans, Interneurons, Nerve Net, Neural Inhibition, Synaptic Transmission, Neuronal Plasticity, Neurons, Parvalbumins, Schizophrenia, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Pyramidal Cells, Receptors, GABA, Receptors, AMPA, Glutamic Acid
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