The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia
Open accessAbstract
OBJECTIVE: Deficient excitatory drive to parvalbumin-containing cortical interneurons is proposed as a key neural substrate for altered gamma oscillations and cognitive dysfunction in schizophrenia. However, a pathological entity producing such a deficit has not been identified. The authors tested the hypothesis that cortical parvalbumin interneurons receive fewer excitatory synaptic inputs in individuals with schizophrenia. METHOD: Fluorescent immunohistochemistry, confocal microscopy, and post-image processing techniques were used to quantify the number of putative excitatory synapses (i.e., the overlap of vesicular glutamate transporter 1-positive [VGlut1+] puncta and postsynaptic density protein 95-positive [PSD95+] puncta) per surface area of parvalbumin-positive (PV+) or calretinin-positive (CR+) neurons in the dorsolateral prefrontal cortex from schizophrenia subjects and matched unaffected comparison subjects. RESULTS: Mean density of VGlut1+/PSD95+ puncta on PV+ neurons was 18% lower in schizophrenia, a significant difference. This deficit was not influenced by methodological confounds or schizophrenia-associated comorbid factors, not present in monkeys chronically exposed to antipsychotic medications, and not present in CR+ neurons. Mean density of VGlut1+/PSD95+ puncta on PV+ neurons predicted the activity-dependent expression levels of parvalbumin and glutamic acid decarboxylase 67 (GAD67) in schizophrenia subjects but not comparison subjects. CONCLUSIONS: To the authors' knowledge, this is the first demonstration that excitatory synapse density is lower selectively on parvalbumin interneurons in schizophrenia and predicts the activity-dependent down-regulation of parvalbumin and GAD67. Because the activity of parvalbumin interneurons is required for generation of cortical gamma oscillations and working memory function, these findings reveal a novel pathological substrate for cortical dysfunction and cognitive deficits in schizophrenia.
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“Furthermore, individuals with schizophrenia have a lower density of excitatory synapses on PV-INs [12] and exhibit alterations in gamma oscillations during a working memory task [13].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [12]
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Cites
A Computational Approach to Edge Detection
Canny, J. (1986) · IEEE Transactions on Pattern Analysis and Machine Intelligence · doi:10.1109/tpami.1986.4767851 · Cited by 30,004 · cited 2×
“Edges of PV+ or CR+ cell bodies were segmented by the MATLAB edge function using the Canny edge detector operator(30).”
BackgroundMethodParvalbumin neurons and gamma rhythms enhance cortical circuit performance
Sohal, V. S., Zhang, F., Yizhar, O., & Deisseroth, K. (2009) · Nature · doi:10.1038/nature07991 · Cited by 2,606 · cited 1×
“Because cortical gamma oscillations require the activity of parvalbumin-containing (PV) interneurons(4, 5), deficient cortical PV interneuron activity could provide the neural substrate for altered prefrontal gamma oscillations and consequently impaired working memory in schizophrenia.”
BackgroundDriving fast-spiking cells induces gamma rhythm and controls sensory responses
Cardin, J. A., Carlén, M., Meletis, K., Knoblich, U., Zhang, F., Deisseroth, K., Tsai, L.-H., & Moore, C. I. (2009) · Nature · doi:10.1038/nature08002 · Cited by 2,603 · cited 1×
“Because cortical gamma oscillations require the activity of parvalbumin-containing (PV) interneurons(4, 5), deficient cortical PV interneuron activity could provide the neural substrate for altered prefrontal gamma oscillations and consequently impaired working memory in schizophrenia.”
BackgroundAbnormal neural oscillations and synchrony in schizophrenia
Uhlhaas, P. J., & Singer, W. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2774 · Cited by 2,120 · cited 16×
“Excitatory synapses on PV interneurons predict PV and GAD67 expression levels in human DLPFC Finally, we assessed whether the density of excitatory synapses on PV+ neurons predicted levels of PV and GAD67, molecular markers of PV interneuron activity.”
BackgroundInfluentialThe Expression of Vesicular Glutamate Transporters Defines Two Classes of Excitatory Synapse
Fremeau, R. T., Troyer, M. D., Pahner, I., Nygaard, G. O., Tran, C. H., Reimer, R. J., Bellocchio, E. E., Fortin, D. L., Storm‐Mathisen, J., & Edwards, R. H. (2001) · Neuron · doi:10.1016/s0896-6273(01)00344-0 · Cited by 1,266 · cited 1×
“First, we did not sample vesicular glutamate transporter 2-containing excitatory inputs that represent projections from the thalamus(40).”
BackgroundAkbarian, S. (1995) · Archives of General Psychiatry · doi:10.1001/archpsyc.1995.03950160008002 · Cited by 1,002 · cited 1×
“Consistent with this hypothesis, postmortem studies have repeatedly shown lower PV and GAD67 levels in the DLPFC of schizophrenia subjects(13-17), which are thought to reflect lower glutamatergic drive to a subset of PV neurons and not a loss of PV neurons in the illness(13, 15, 18, 19).”
ResultHashimoto, T., Volk, D. W., Eggan, S. M., Mirnics, K., Pierri, J. N., Sun, Z., Sampson, A. R., & Lewis, D. A. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-15-06315.2003 · Cited by 938 · cited 4×
“These deficits do not seem to be due to a global reduction in excitatory drive to all interneuron subtypes, as calretinin-containing (CR) interneurons, the most abundant interneuron subtype in the primate DLPFC(20), appear to be relatively unaffected in schizophrenia(15, 16, 21).”
BackgroundMethodResultInfluentialSelf-citationSchizophrenia Is a Cognitive Illness: Time for a Change in Focus
Kahn, R. S., & Keefe, R. S. E. (2013) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.155 · Cited by 825 · cited 1×
“Cognitive dysfunction is a core and clinically-critical feature of schizophrenia(1) but responds poorly to available medications(2).”
BackgroundPostnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes
Belforte, J. E., Zsiros, V., Sklar, E. R., Jiang, Z., Yu, G., Li, Y., Quinlan, E. M., & Nakazawa, K. (2010) · Nature Neuroscience · doi:10.1038/nn.2447 · Cited by 752 · cited 1×
“, PV and the GABA-synthesizing enzyme glutamic acid decarboxylase 67, GAD67), abnormal gamma oscillations and working memory deficits(9-12).”
BackgroundParvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning
Donato, F., Rompani, S. B., & Caroni, P. (2013) · Nature · doi:10.1038/nature12866 · Cited by 703 · cited 1×
“VGlut1+ and PSD95+ puncta were used to identify the pre- and postsynaptic elements, respectively, as these molecular markers have been previously used to define excitatory synapses in PV interneurons(11, 28, 29).”
Method
Research works printed but not linked: 3
- Enwright JF, Neuropsychopharmacology
- Rocco BR, Biol Psychiatry
- Georgiev D, Schizophr Bull
Cited by
Sorted by citations
Alterations in cortical interneurons and cognitive function in schizophrenia
Dienel, S. J., & Lewis, D. A. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.06.020 · Cited by 281
Self-citationSmucny, J., Dienel, S. J., Lewis, D. A., & Carter, C. S. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01089-0 · Cited by 231
“Furthermore, findings of altered ErbB4 splicing [189], and an associated deficit in the density of excitatory inputs onto PV neurons [159], suggest the possibility of a primary pathological process in PV neurons.”
BackgroundSelf-citationParvalbumin interneuron vulnerability and brain disorders
Ruden, J. B., Dugan, L. L., & Konradi, C. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-020-0778-9 · Cited by 194
“Furthermore, individuals with schizophrenia have a lower density of excitatory synapses on PV-INs [12] and exhibit alterations in gamma oscillations during a working memory task [13].”
BackgroundKrystal, J. H., Anticevic, A., Yang, G., Dragoi, G., Driesen, N. R., Wang, X., & Murray, J. D. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.01.004 · Cited by 201
“Recent data suggest that deficits in GABA neuronal function associated with schizophrenia arise as a consequence of deficient excitatory input (53) or responsivity to this input (54) and serve to reduce inhibition in cortical microcircuits in ways that compensate for reduced excitatory connectivity (55).”
BackgroundLong-Lasting Rescue of Network and Cognitive Dysfunction in a Genetic Schizophrenia Model
Mukherjee, A., Carvalho, F., Eliez, S., & Caroni, P. (2019) · Cell · doi:10.1016/j.cell.2019.07.023 · Cited by 169
Metadata
- Authors
- Chung, D. W., Fish, K. N., & Lewis, D. A.
- Affiliations
- University of Pittsburgh (US)
- Venue
- American Journal of Psychiatry
- Published
- 2016-11-01
- Volume
- 173
- Issue
- 11
- Pages
- 1131-1139
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC5089927
- OpenAlex
- W2490214293
- Cited by
- 148
- References
- 55
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 16 · 2023: 11 · 2022: 14 · 2021: 18 · 2020: 14 · 2019: 14 · 2018: 20 · 2017: 16 · 2016: 1
- FWCI
- 15.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH043784, P50MH103204, R01MH096985, R37MH043784)
- 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 › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, parvalbumin interneurons, glutamatergic synapses, VGLUT1, PSD-95, calretinin interneurons, dorsolateral prefrontal cortex, GAD67, gamma oscillations, working memory, cognitive impairment
- MeSH terms
- Disks Large Homolog 4 Protein, Adult, Animals, Female, Glutamate Decarboxylase, Humans, Interneurons, Macaca fascicularis, Male, Membrane Proteins, Middle Aged, Parvalbumins, Schizophrenia, Antipsychotic Agents, Case-Control Studies, Prefrontal Cortex, Intracellular Signaling Peptides and Proteins, Vesicular Glutamate Transport Protein 1, Calbindin 2
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