Glutamate Receptor Subtypes Mediating Synaptic Activation of Prefrontal Cortex Neurons: Relevance for Schizophrenia
Open accessAbstract
Schizophrenia may involve hypofunction of NMDA receptor (NMDAR)-mediated signaling, and alterations in parvalbumin-positive fast-spiking (FS) GABA neurons that may cause abnormal gamma oscillations. It was recently hypothesized that prefrontal cortex (PFC) FS neuron activity is highly dependent on NMDAR activation and that, consequently, FS neuron dysfunction in schizophrenia is secondary to NMDAR hypofunction. However, NMDARs are abundant in synapses onto PFC pyramidal neurons; thus, a key question is whether FS neuron or pyramidal cell activation is more dependent on NMDARs. We examined the AMPAR and NMDAR contribution to synaptic activation of FS neurons and pyramidal cells in the PFC of adult mice. In FS neurons, EPSCs had fast decay and weak NMDAR contribution, whereas in pyramidal cells, EPSCs were significantly prolonged by NMDAR-mediated currents. Moreover, the AMPAR/NMDAR EPSC ratio was higher in FS cells. NMDAR antagonists decreased EPSPs and EPSP–spike coupling more strongly in pyramidal cells than in FS neurons, showing that FS neuron activation is less NMDAR dependent than pyramidal cell excitation. The precise EPSP–spike coupling produced by fast-decaying EPSCs in FS cells may be important for network mechanisms of gamma oscillations based on feedback inhibition. To test this possibility, we used simulations in a computational network of reciprocally connected FS neurons and pyramidal cells and found that brief AMPAR-mediated FS neuron activation is crucial to synchronize, via feedback inhibition, pyramidal cells in the gamma frequency band. Our results raise interesting questions about the mechanisms that might link NMDAR hypofunction to alterations of FS neurons in schizophrenia.
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The AMPAR/NMDAR ratio differs between pyramidal cells and fast-spiking interneurons.
“This is important in light of recent studies showing that the AMPAR/NMDAR ratio differs between pyramidal cells and fast-spiking interneurons (Wang and Gao 2009;Rotaru et al. 2011).”
From Linking microcircuit dysfunction to cognitive impairment: Effects of disinhibition associated with schizophrenia in a cortical working memory model (2014) · cites this paper as Rotaru et al. 2011
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- Authors
- Rotaru, D. C., Yoshino, H., Lewis, D. A., Ermentrout, G. B., & Gonzalez-Burgos, G.
- Affiliations
- University of Pittsburgh (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-01-05
- Volume
- 31
- Issue
- 1
- Pages
- 142-156
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3041270
- OpenAlex
- W1988282606
- Cited by
- 151
- References
- 127
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 8 · 2020: 7 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 10 · 2015: 15 · 2014: 14 · 2013: 15 · 2012: 14
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- SK Life Science
- National Institutes of Health (MH084053)
- National Institute of Mental Health (P50MH084053, MH084053, R01MH043784)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- schizophrenia, NMDA receptor hypofunction, prefrontal cortex, pyramidal neurons, AMPA receptors, glutamate receptor subtypes, synaptic excitation, gamma oscillations, product inhibition
- MeSH terms
- Action Potentials, Animals, Biophysics, Computer Simulation, Electric Stimulation, Female, Lysine, Male, Membrane Potentials, Mice, Inbred C57BL, Models, Neurological, Neurons, Probability, Pyridazines, Synapses, Prefrontal Cortex, Receptors, Glutamate, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Statistics, Nonparametric, GABA Antagonists, Excitatory Postsynaptic Potentials, Mice, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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