Downregulation of Parvalbumin at Cortical GABA Synapses Reduces Network Gamma Oscillatory Activity
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Postmortem and functional imaging studies of patients with psychiatric disorders, including schizophrenia, are consistent with a dysfunction of interneurons leading to compromised inhibitory control of network activity. Parvalbumin (PV)-expressing, fast-spiking interneurons interacting with pyramidal neurons generate cortical gamma oscillations (30–80 Hz) that synchronize cortical activity during cognitive processing. In postmortem studies of schizophrenia patients, these interneurons show reduced PV and glutamic acid decarboxylase 67 (GAD67), an enzyme that synthesizes GABA, but the consequences of this downregulation are unclear. We developed a biophysically realistic and detailed computational model of a cortical circuit including asynchronous release from GABAergic interneurons to investigate how reductions in PV and GABA affect gamma oscillations induced by sensory stimuli. Networks with reduced GABA were disinhibited and had altered gamma oscillations in response to stimulation; PV-deficient GABA synapses had increased asynchronous release of GABA, which decreased the level of excitation and reduced gamma-band activity. Combined reductions of PV and GABA resulted in a diminished gamma-band oscillatory activity in response to stimuli, similar to that observed in schizophrenia patients. Our results suggest a mechanism by which reduced GAD67 and PV in fast-spiking interneurons may contribute to cortical dysfunction in schizophrenia and related psychiatric disorders.
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Stimulating PV-INs increases gamma oscillation patterns, whereas inhibiting PV-INs or downregulating PV at cortical synapses reduces gamma oscillations.
“Stimulation of PV-INs leads to an increase in gamma oscillation patterns, while inhibition of PV-INs or downregulation of PV at cortical synapses reduces gamma oscillations [76][77][78].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [78]
Recent advances in computational neuroscience have shown that properties of neural circuits can be captured by large-scale models that successfully predict the relationship between parameters of E/I balance and the occurrence of gamma-band oscillations.
“Recent advances in computational neuroscience have shown that properties of neural circuits can be captured by large-scale models that successfully predict, for example, the relationship between parameters of E/I balance and the occurrence of gamma-band oscillations (Neymotin et al., 2011”
From Neuronal Dynamics and Neuropsychiatric Disorders: Toward a Translational Paradigm for Dysfunctional Large-Scale Networks (2012) · cites this paper as Volman et al., 2011
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- Authors
- Volman, V., Behrens, M. M., & Sejnowski, T. J.
- Affiliations
- Salk Institute for Biological Studies (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-12-07
- Volume
- 31
- Issue
- 49
- Pages
- 18137-18148
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3257321
- OpenAlex
- W2092726530
- Semantic Scholar
- 8856dc2fc5afcdd1f2cff5f3097eafc6570f0a07
- Cited by
- 164
- References
- 61
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 6 · 2023: 3 · 2022: 12 · 2021: 11 · 2020: 8 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 6 · 2015: 17 · 2014: 19 · 2013: 25 · 2012: 17
- FWCI
- 9.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (0822283)
- Howard Hughes Medical Institute
- National Institutes of Health (5r01ns059740-04)
- University of California, San Diego (PHY-0822283)
- National Institute of Mental Health (R01MH091407, MH091407)
- National Institute of Neurological Disorders and Stroke (R01-NS-059740, NS059740)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- parvalbumin, fast-spiking interneurons, gamma oscillations, GABAergic synapses, glutamic acid decarboxylase 67, schizophrenia, cortical inhibition, asynchronous neurotransmitter release, computational neural network model
- MeSH terms
- Action Potentials, Biological Clocks, Cerebral Cortex, Computer Simulation, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Humans, Interneurons, Models, Neurological, Nerve Net, Parvalbumins, Physical Stimulation, Synapses, Down-Regulation, Nonlinear Dynamics
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