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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People with schizophrenia have a lower density of excitatory synapses on PV-INs.
“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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“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.”
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“Both an abnormal shift in ErbB4 splicing at the JM locus(45, 46) and lower Narp transcript levels have been shown in the DLPFC of subjects with schizophrenia, including those included in the present study(21, 47).”
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Alterations in cortical interneurons and cognitive function in schizophrenia
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“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.”
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Pre-frontal parvalbumin interneurons in schizophrenia: a meta-analysis of post-mortem studies
Kaar, S. J., Angelescu, I., Marques, T. R., & Howes, O. D. (2019) · Journal of Neural Transmission · doi:10.1007/s00702-019-02080-2 · Cited by 146 · see citing works
van Berlekom, A. B., Muflihah, C. H., Snijders, G. J. L., MacGillavry, H. D., Middeldorp, J., Hol, E. M., Kahn, R. S., & de Witte, L. D. (2019) · Schizophrenia Bulletin · doi:10.1093/schbul/sbz060 · Cited by 149 · see citing works
Forsyth, J. K., & Lewis, D. A. (2017) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2017.06.006 · Cited by 143 · see citing works
Self-citationNeuronal survival in the brain: neuron type-specific mechanisms
Pfisterer, U., & Khodosevich, K. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.64 · Cited by 139 · see citing works
“In addition, it might be that the strength of marker expression rather than the number of neurons is affected.(140) Although knockout/knockdown of genes that are associated with psychiatric disorders has been reported to decrease the number of immature neurons in mice,(141) other studies showed that maturation rather…”
BackgroundUpper cortical layer–driven network impairment in schizophrenia
Batiuk, M. Y., Tyler, T., Dragičević, K., Mei, S., Rydbirk, R., Petukhov, V., Deviatiiarov, R. M., Sedmak, D., Frank, E., Feher, V., et al. (2022) · Science Advances · doi:10.1126/sciadv.abn8367 · Cited by 141 · see citing works
Distinct Physiological Maturation of Parvalbumin-Positive Neuron Subtypes in Mouse Prefrontal Cortex
Miyamae, T., Chen, K., Lewis, D. A., & González‐Burgos, G. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3325-16.2017 · Cited by 129 · see citing works
“First, our data suggest that the deficit of excitatory synapses in PV neurons in schizophrenia (Chung et al., 2016), if produced during development, may disrupt the FS phenotype.”
BackgroundSelf-citationCurrent findings and perspectives on aberrant neural oscillations in schizophrenia
Hirano, Y., & Uhlhaas, P. J. (2021) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13300 · Cited by 121 · see citing works
The Role of Parvalbumin Interneurons in Neurotransmitter Balance and Neurological Disease
Nahar, L., Delacroix, B. M., & Nam, H. W. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.679960 · Cited by 118 · see citing works
“These results also corresponded to deficits in GAD67, suggesting amore precise and cell-type-specific mechanism of cortical dysfunction and cognitive deficit that occurs in schizophrenia (49).”
ResultShao, Z., Noh, H., Kim, W. B., Ni, P., Nguyen, C. L., Cote, S. E., Noyes, E. A., Zhao, J., Parsons, T. J., Park, J. M., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0313-z · Cited by 111 · see citing works
Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia
Nakazawa, K., Jeevakumar, V., & Nakao, K. (2017) · npj Schizophrenia · doi:10.1038/s41537-016-0003-3 · Cited by 110 · see citing works
“Another postmortem study demonstrated a lower density of excitatory synapses on PVpositive interneurons in PFC of patients with schizophrenia, while the glutamate receptor subtypes were unidentified.(120) This could be due to a deficit in excitatory synapse formation on PV neurons, or due to reduced synaptic input fro…”
BackgroundProtective role of IGF-1 and GLP-1 signaling activation in neurological dysfunctions
Bhalla, S., Mehan, S., Khan, A., & Rehman, M. U. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104896 · Cited by 108 · see citing works
Kokkinou, M., Irvine, E. E., Bonsall, D. R., Natesan, S., Wells, L. A., Smith, M., Glegola, J. A., Paul, E. J., Tossell, K., Veronese, M., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0740-6 · Cited by 105 · see citing works
Adams, R. A., Pinotsis, D., Tsirlis, K., Unruh, L., Mahajan, A., Horas, A. M., Convertino, L., Summerfelt, A., Sampath, H., Du, X. M., et al. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.07.024 · Cited by 98 · see citing works
“, reduced function of NMDA (1,2,6), dopamine D1 (9), and muscarinic (10) receptors] and inhibitory interneurons downregulated (4,5), then the most logical interpretation of increases and decreases in pyramidal self-inhibition is diminished pyramidal synaptic gain (41,42) and decreased interneuron function, respectivel…”
Page, C. E., & Coutellier, L. D. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.08.030 · Cited by 95 · see citing works
Neural circuit dysfunction in mouse models of neurodevelopmental disorders
del Pino, I., Rico, B., & Marín, Ó. (2018) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.12.013 · Cited by 94 · see citing works
“Human postmortem studies have identified synaptic deficits in fast spiking interneurons [22,23], a population of GABAergic cells that are involved in the modulation of gamma rhythms and working memory [24].”
Cytosolic Ca 2+ Buffers Are Inherently Ca 2+ Signal ModulatorsPreprint
Schwaller, B. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a035543 · Cited by 90 · see citing works
“In line with the NMDA-R hypofunction hypothesis in schizophrenia, the number of putative excitatory synapses (puncta with overlap of presynaptic VGlut1 and postsynaptic PSD95) are 18% lower in dlPFC Pvalb neurons of schizophrenia subjects (Chung et al. 2016).”
BackgroundUmezawa, M., Onoda, A., Korshunova, I., Jensen, A. C. Ø., Koponen, I. K., Jensen, K. A., Khodosevich, K., Vogel, U. B., & Hougaard, K. S. (2018) · Particle and Fibre Toxicology · doi:10.1186/s12989-018-0272-2 · Cited by 86 · see citing works
Alterations of Astrocytes in the Context of Schizophrenic Dementia
Tarasov, V. V., Svistunov, A. А., Chubarev, V. N., Sologova, S. S., Мухортова, П. А., Levushkin, D., Somasundaram, S. G., Kirkland, C. E., Бачурин, С. О., & Aliev, G. M. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01612 · Cited by 84 · see citing works
“The reason for the decrease in the activity of parvalbumin neurons in schizophrenia patients in the reduced access to glutamate (Chung et al., 2016).”
BackgroundDienel, S. J., Schoonover, K. E., & Lewis, D. A. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.03.002 · Cited by 81 · see citing works
Self-citationGrent-‘t-Jong, T., Gajwani, R., Groß, J., Gumley, A. I., Krishnadas, R., Lawrie, S. M., Schwannauer, M., Schultze‐Lutter, F., & Uhlhaas, P. J. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.03.018 · Cited by 79 · see citing works
“In addition, evidence exists that impaired inhibition could be the result of NMDAR hypofunctioning on PV1 interneurons (57) or reduced NMDAR drive on pyramidal cells (58).”
The tetrapartite synapse: a key concept in the pathophysiology of schizophrenia
Chelini, G., Pantazopoulos, H., Durning, P. T., & Berretta, S. (2018) · European Psychiatry · doi:10.1016/j.eurpsy.2018.02.003 · Cited by 73 · see citing works
Gao, W., Yang, S.-S., Mack, N. R., & Chamberlin, L. A. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01196-w · Cited by 70 · see citing works
Dienel, S. J., Fish, K. N., & Lewis, D. A. (2023) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20220676 · Cited by 71 · see citing works
Self-citationParvalbumin interneuron deficits in schizophrenia
Marín, Ó. (2024) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2024.02.010 · Cited by 72 · see citing works
“In agreement with this idea, the density of excitatory synapses contacting PV + interneurons in the prefrontal cortex is lower in schizophrenia patients than in controls (Chung et al., 2016).”
BackgroundParvalbumin and GABA Microcircuits in the Mouse Superior Colliculus
Villalobos, C. A., Wu, Q., Lee, P. H., May, P. J., & Basso, M. A. (2018) · Frontiers in Neural Circuits · doi:10.3389/fncir.2018.00035 · Cited by 62 · see citing works
“…to the function of PV+ neurons are associated with disorders ranging from autism to schizophrenia, highlighting the importance of PV+ neurons in mechanisms underlying higher cognitive functions (Lewis et al., 2012; Wöhr et al., 2015; Chung et al., 2016; Hashemi et al., 2017; Kim et al., 2017).”
BackgroundChung, D. W., Wills, Z. P., Fish, K. N., & Lewis, D. A. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1610077114 · Cited by 59 · see citing works
“In the DLFPC of individuals with schizophrenia, a pathogenic shift in ErbB4 splicing from the JM-b to JM-a variants has been associated with fewer excitatory synaptic inputs to PV interneurons (26, 28), which could reflect an exaggerated pruning process in these neurons.”
BackgroundMethodResultInfluentialSelf-citationRegion-specific impairments in parvalbumin interneurons in social isolation-reared mice
Ueno, H., Suemitsu, S., Murakami, S., Kitamura, N., Wani, K., Okamoto, M., Matsumoto, Y., & Ishihara, T. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.07.016 · Cited by 56 · see citing works
“A number of recent studies have shown that the functional deterioration of PV neurons is involved in the onset of schizophrenia and autism spectrum disorders (Beasley and Reynolds, 1997; Lawrence et al., 2010; Lewis, 2014; Chung et al., 2016; Hiroshi Ueno et al. 18 Hashemi et al., 2016).”
BackgroundResultGrent-‘t-Jong, T., Brickwedde, M., Metzner, C., & Uhlhaas, P. J. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.03.026 · Cited by 57 · see citing works
“with recent postmortem data (100) that have indicated that reductions in PV1 interneurons may constitute an adaptive response to decreased excitatory drive.”
Mapping pathologic circuitry in schizophrenia
Glausier, J. R., & Lewis, D. A. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-63639-3.00025-6 · Cited by 52 · see citing works
Self-citationChung, D., Chung, Y., Bazmi, H., & Lewis, D. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0169-7 · Cited by 50 · see citing works
Self-citationPatrono, E., Svoboda, J., & Stuchlı́k, A. (2021) · Behavioral and Brain Functions · doi:10.1186/s12993-021-00180-2 · Cited by 55 · see citing works
Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders
Exposito-Alonso, D., & Rico, B. (2022) · Annual Review of Genetics · doi:10.1146/annurev-genet-072820-023642 · Cited by 49 · see citing works
Tsubomoto, M., Kawabata, R., Zhu, X., Minabe, Y., Chen, K., Lewis, D. A., & Hashimoto, T. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy227 · Cited by 52 · see citing works
“In addition, recent studies using quantitative immunohistochemistry revealed reduced GAD67 and PV protein levels and unaltered CR protein levels in the left DLPFC of schizophrenia subjects (Curley et al. 2011; Enwright et al. 2016; Rocco et al. 2016; Chung et al. 2016a).”
BackgroundSelf-citationGABA and schizophrenia: Where we stand and where we need to go
Glausier, J. R., & Lewis, D. A. (2017) · Schizophrenia Research · doi:10.1016/j.schres.2017.01.050 · Cited by 49 · see citing works
Self-citationDisinhibition, an emerging pharmacology of learning and memory
Möhler, H., & Rudolph, U. (2017) · F1000Research · doi:10.12688/f1000research.9947.1 · Cited by 44 · see citing works
Prenatal inflammation and risk for schizophrenia: A role for immune proteins in neurodevelopment
Allswede, D. M., & Cannon, T. D. (2018) · Development and Psychopathology · doi:10.1017/s0954579418000317 · Cited by 45 · see citing works
Gooch, H. M., Cui, X., Anggono, V., Trzaskowski, M., Tan, M. C., Eyles, D. W., Burne, T. H. J., Jang, S. E., Mattheisen, M., HOUGAARD, D. M., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0626-z · Cited by 44 · see citing works
Schoonover, K. E., Dienel, S. J., & Lewis, D. A. (2020) · Biomarkers in Neuropsychiatry · doi:10.1016/j.bionps.2020.100015 · Cited by 44 · see citing works
“The deficits in PV mRNA are accompanied by comparable decrements in levels of PV protein in cell bodies [118] and axon terminals [119].”
BackgroundSelf-citationFine structure analysis of perineuronal nets in the ketamine model of schizophrenia
Kaushik, R., Lipachev, N., Matuszko, G., Kochneva, A., Dvoeglazova, A., Becker, A., Николаевич, П. М., & Dityatev, A. E. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14853 · Cited by 41 · see citing works
“…Bitanihirwe & Woo, 2014a; Reynolds, Beasley, & Zhang, 2002; Sakai et al., 2008), while other reported no changes in the density of PV+ interneurons (Alcaide et al., 2019; Chung et al., 2016; Enwright et al., 2016; Hashimoto et al., 2003; Tooney & Chahl, 2004; Woo, Miller, & Lewis, 1997).”
Toader, O., von Heimendahl, M., Schuelert, N., Nissen, W., & Rosenbrock, H. (2019) · Schizophrenia Bulletin · doi:10.1093/schbul/sbz123 · Cited by 37 · see citing works
Fish, K. N., Rocco, B. R., DeDionisio, A. M., Dienel, S. J., Sweet, R. A., & Lewis, D. A. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.02.009 · Cited by 38 · see citing works
Self-citationSynaptic Variability and Cortical Gamma Oscillation Power in Schizophrenia
Chung, D. W., Geramita, M. A., & Lewis, D. A. (2022) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2021.21080798 · Cited by 37 · see citing works
Self-citationDatta, D., & Arnsten, A. F. T. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.7b00505 · Cited by 36 · see citing works
Pafundo, D. E., Miyamae, T., Lewis, D. A., & González‐Burgos, G. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.01.018 · Cited by 37 · see citing works
“Parvalbumin-positive (PV) interneurons are a major source of inhibitory inputs on PCs (7), and 58 PV neuron alterations may contribute to PFC microcircuit dysfunction in schizophrenia (8-10).”
BackgroundMethodSelf-citationA postnatal molecular switch drives activity-dependent maturation of parvalbumin interneurons
Moissidis, M., Abbasova, L., Selten, M. M., Alis, R., Bernard, C., Domínguez-Canterla, Y., Oozeer, F., Qin, S., Kelly, A., Mòdol, L., et al. (2025) · Cell · doi:10.1016/j.cell.2025.06.029 · Cited by 34 · see citing works
NECAB1 and NECAB2 are Prevalent Calcium-Binding Proteins of CB1/CCK-Positive GABAergic Interneurons
Miczán, V., Kelemen, K., Glavinics, J. R., László, Z. I., Barti, B., Kenesei, K., Kisfali, M., & Katona, I. (2020) · Cerebral Cortex · doi:10.1093/cercor/bhaa326 · Cited by 29 · see citing works
Sanz‐Morello, B., Pfisterer, U., Hansen, N. W., Demharter, S., Thakur, A., Fujii, K., Левицкий, С. А., Montalant, A., Korshunova, I., Mammen, P. P. A., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020105759 · Cited by 33 · see citing works
“Such vulnerability to oxidative stress, which is especially pronounced during brain maturation (Behrens & Sejnowski, 2009), could lead to a selective dysfunction of PV + interneurons in mental disorders (Chung et al , 2016; Steullet et al , 2017; Vasistha et al , 2019).”
Treatment with levetiracetam improves cognition in a ketamine rat model of schizophrenia
Koh, M. T., Shao, Y., Rosenzweig-Lipson, S. J., & Gallagher, M. (2017) · Schizophrenia Research · doi:10.1016/j.schres.2017.06.027 · Cited by 33 · see citing works
“Recent evidence has implicated deficient inhibitory control involving parvalbumin interneurons in the cortex (Chung et al., 2016; Krystal et al., 2017), which has also been proposed as a basis for impairment in models of Alzheimer’s disease pathology (Palop and Mucke, 2016).”
Garst-Orozco, J., Malik, R., Lanz, T. A., Weber, M. L., Xi, H. S., Arion, D., Enwright, J. F., Lewis, D. A., O’Donnell, P., Sohal, V. S., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0233895 · Cited by 32 · see citing works
“Reduced expression of GAD67 protein has been found in parvalbumin interneuron terminals [31], and a reduction in mean parvalbumin intensity has been measured in parvalbumin interneurons in schizophrenia without an alteration in PV neuron density [32].”
BackgroundSelf-citationParnell, E., Culotta, L., Forrest, M. P., Jalloul, H. A., Eckman, B. L., Loizzo, D. D., Horan, K. E., Santos, M. D., Piguel, N. H., Tai, D. J. C., et al. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.11.005 · Cited by 29 · see citing works
“Moreover, these deficits were dependent on impaired glutamatergic neuronal activity, supporting previous assertions of excitatory dysfunction as a driver of deficits in SCZ (66,67).”
Dienel, S. J., Enwright, J. F., Hoftman, G. D., & Lewis, D. A. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.06.003 · Cited by 31 · see citing works
“…not uniform across all cell types; for example, PV-containing GABA neurons are clearly affected in schizophrenia, whereas calretinin-containing GABA neurons appear to be unaffected (Chung et al., 2016a, 2016b; Enwright et al., 2018; Fung et al., 2010; Hashimoto et al., 2003; Mellios et al., 2009).”
BackgroundSelf-citation40 Hz Steady-State Response in Human Auditory Cortex Is Shaped by Gabaergic Neuronal Inhibition
Toso, A., Wermuth, A. P., Arazi, A., Braun, A., Grent-‘t-Jong, T., Uhlhaas, P. J., & Donner, T. H. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.2029-23.2024 · Cited by 30 · see citing works
Khaleghi, A., Mohammadi, M. R., Shahi, K., & Nasrabadi, A. M. (2023) · Iranian Journal of Psychiatry · doi:10.18502/ijps.v18i2.12363 · Cited by 29 · see citing works
“Given that the expression of PVIs and GAD67 is dependent on the activity, GABAergic drive is decreased within the prefrontal cortex in schizophrenia (39).”
BackgroundPage, C. E., Alexander, J., Shepard, R. M., & Coutellier, L. D. (2018) · Genes Brain & Behavior · doi:10.1111/gbb.12459 · Cited by 29 · see citing works
Neural and neuronal discoordination in schizophrenia: from ensembles through networks to symptoms
Krajcovic, B., Fajnerova, I., Horacek, J., Kelemen, E., Kubik, S., Svoboda, J., & Stuchlik, A. (2019) · Acta Physiologica · doi:10.1111/apha.13282 · Cited by 29 · see citing works
Ketamine Alters Lateral Prefrontal Oscillations in a Rule-Based Working Memory Task
Ma, L., Skoblenick, K. J., Johnston, K., & Everling, S. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2659-17.2018 · Cited by 24 · see citing works
“In patients with schizophrenia, PV neurons lose excitatory synapses with the progression of the disease (Chung et al., 2016).”
BackgroundAdotevi, N. K., & Leitch, B. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00434 · Cited by 25 · see citing works
“Another mechanism for a reduction in excitatory drive onto PV neurons could be a reduction in the number of excitatory synapses onto these neurons (as occurs in schizophrenia, Chung et al., 2016).”
BackgroundFernández‐Teruel, A., Oliveras, I., Cañete, T., Río-Álamos, C., Tapias-Espinosa, C., Sampedro-Viana, D., Sánchez-González, A., Sanna, F., Torrúbia, R., González‐Maeso, J., et al. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.09.042 · Cited by 24 · see citing works
de Bartolomeis, A., Ciccarelli, M., Simone, G. D., Mazza, B., Barone, A., & Vellucci, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065945 · Cited by 25 · see citing works
Visual Attention Decits in Schizophrenia Can Arise From Inhibitory Dysfunction in Thalamus or Cortex
John, Y. J., Zikopoulos, B., Bullock, D. H., & Barbas, H. (2018) · Computational Psychiatry · doi:10.1162/cpsy_a_00023 · Cited by 23 · see citing works
de Bartolomeis, A., Simone, G. D., Ciccarelli, M., Castiello, A., Mazza, B., Vellucci, L., & Barone, A. (2022) · Biomedicines · doi:10.3390/biomedicines10123183 · Cited by 26 · see citing works
“Other studies proved an alteration of PSD-95 protein expression also in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia [63,64].”
BackgroundNpas4 deficiency and prenatal stress interact to affect social recognition in mice
Heslin, K. A., & Coutellier, L. D. (2017) · Genes Brain & Behavior · doi:10.1111/gbb.12448 · Cited by 24 · see citing works
Sánchez-González, A., Thougaard, E., Tapias-Espinosa, C., Cañete, T., Sampedro-Viana, D., Saunders, J. M., Toneatti, R., Tobeña, A., González‐Maeso, J., Aznar, S., et al. (2021) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2021.01.006 · Cited by 21 · see citing works
“In schizophrenia brains, lower PV mRNA expression and density of PVimmunoreactive puncta are reported despite intact numbers of PV interneurons (Chung et al., 2016;Glausier et al., 2014;Enwright et al., 2016;Beasley et al., 2002).”
BackgroundLi, J., Loebel, A. D., & Meltzer, H. Y. (2018) · Schizophrenia Research · doi:10.1016/j.schres.2018.04.006 · Cited by 21 · see citing works
Hughes, H., Brady, L. J., & Schoonover, K. E. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1440834 · Cited by 20 · see citing works
Nie, J., Wei, X., Xu, X., Li, N., Li, Y., Zhao, Y., Guan, Y., Ge, F., & Guan, X. (2020) · The FASEB Journal · doi:10.1096/fj.202000346rr · Cited by 20 · see citing works
Kurachi, M., Takahashi, T., Sumiyoshi, T., Uehara, T., & Suzuki, M. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00039 · Cited by 20 · see citing works
“(107) demonstrated that the excitatory synapse density is selectively lower on parvalbumin interneurons in schizophrenia patients and that this may lead to the alterations of cortical gamma oscillations and working memory dysfunction.”
BackgroundWang, Y., Fasching, L., Wu, F., Šuvakov, M., Huttner, A. J., Berretta, S., Roberts, R. C., Leckman, J. F., Fernandez, T. V., Abyzov, A. S., et al. (2025) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.12.022 · Cited by 19 · see citing works
Wang, T., Sinha, A. S., Akita, T., Yanagawa, Y., & Fukuda, A. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00284 · Cited by 18 · see citing works
“Altered expression of various GABA-related proteins and/or decreased GABA concentrations in multiple regions of the brain have been reported in postmortem studies of human patients with psychiatric disorders (Akbarian et al., 1995; Yip et al., 2007; Curley et al., 2011; Berretta et al., 2015; Dong et al., 2015; Frankl…”
BackgroundBeyond the γ-aminobutyric acid hypothesis of schizophrenia
Fujihara, K. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1161608 · Cited by 18 · see citing works
Miyamae, T., Hashimoto, T., Abraham, M., Kawabata, R., Koshikizawa, S., Bian, Y., Nishihata, Y., Kikuchi, M., Ermentrout, B., Lewis, D. A., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105382 · Cited by 17 · see citing works
Self-citationThe Scanner as the Stimulus: Deficient Gamma-BOLD Coupling in Schizophrenia at Rest
Jacob, M., Sargent, K., Roach, B. J., Shamshiri, E., Mathalon, D. H., & Ford, J. M. (2023) · Schizophrenia Bulletin · doi:10.1093/schbul/sbad014 · Cited by 17 · see citing works
Fabian, C. B., Jordan, N. D., Cole, R. H., Carley, L. G., Thompson, S. M., Seney, M. L., & Joffe, M. E. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-01889-0 · Cited by 16 · see citing works
Zamberletti, E., & Rubino, T. (2020) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2020.06.013 · Cited by 17 · see citing works
Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia
Chung, Y., Dienel, S. J., Belch, M., Fish, K. N., Ermentrout, B., Lewis, D. A., & Chung, D. W. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02417-8 · Cited by 16 · see citing works
Self-citationThe abiding relevance of mouse models of rare mutations to psychiatric neuroscience and therapeutics
Gogos, J. A., Crabtree, G. W., & Diamantopoulou, A. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.03.018 · Cited by 15 · see citing works
“levels, consistent with findings from human postmortem studies (Chung et al., 2016; Volk et al., 2002).”
ResultDienel, S. J., Ciesielski, A. J., Bazmi, H. H., Profozich, E., Fish, K. N., & Lewis, D. A. (2020) · Cerebral Cortex · doi:10.1093/cercor/bhaa341 · Cited by 15 · see citing works
“In both regions, this finding appears to be due to lower PV mRNA levels per neuron, rather than fewer neurons, in the illness (Woo et al. 1997; Hashimoto et al. 2003; Chung et al. 2016; Enwright et al. 2016).”
BackgroundSelf-citationCalretinin+-neurons-mediated GABAergic inhibition in mouse prefrontal cortex
Saffari, R., Grotefeld, K., Kravchenko, M., Zhang, M., & Zhang, W. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109658 · Cited by 14 · see citing works
KEAP1‐NRF2/HO‐1 Pathway Promotes Ferroptosis and Neuronal Injury in Schizophrenia
Zhu, F., Dan, T., & Hua, S. (2025) · Brain and Behavior · doi:10.1002/brb3.70311 · Cited by 13 · see citing works
“Furthermore, iron dysregulation is linked to ferroptosis, with iron excess promoting oxidative stress through Fenton reactions (Chung, Fish, and Lewis 2016).”
Occhieppo, V. B., Basmadjian, O. M., Marchese, N. A., Jaime, A., Pérez, M. F., Baiardi, G., & Bregonzio, C. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.113809 · Cited by 13 · see citing works
Okamura, K., Yoshino, H., Ogawa, Y., Yamamuro, K., Kimoto, S., Yamaguchi, Y., Nishihata, Y., Ikehara, M., Makinodan, M., Saito, Y., et al. (2022) · Cerebral Cortex · doi:10.1093/cercor/bhac294 · Cited by 13 · see citing works
Fu, J., Liu, F., Qin, W., Xu, Q., Yu, C., & Initiative, A. D. N. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz333 · Cited by 12 · see citing works
“…the PVALB gene was correlated with both brain structure (CCV) and function (resting-state activity) and major mental disorders (ASD, SCZ, and BD), which is in line with the previously reported role of this gene in brain development (Kuchukhidze et al. 2015) and mental disorders (Chung et al. 2016).”
Gee, A., Dazzan, P., Grace, A. A., & Modinos, G. (2025) · Translational Psychiatry · doi:10.1038/s41398-024-03221-2 · Cited by 12 · see citing works
IUPHAR review: Moving beyond dopamine-based therapeutic strategies for schizophrenia
Moran, P. M., & Granger, K. T. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107727 · Cited by 12 · see citing works
Cruz, G., Grent-‘t-Jong, T., Krishnadas, R., Palva, J. M., Palva, S., & Uhlhaas, P. J. (2021) · NeuroImage Clinical · doi:10.1016/j.nicl.2021.102722 · Cited by 11 · see citing works
“, 2004) or reduced NMDA-R drive on pyramidal cells (Chung et al., 2016).”
BackgroundHaikonen, J., Szrinivasan, R., Ojanen, S., Rhee, J. K., Ryazantseva, M., Sulku, J., Zumaraite, G., & Lauri, S. E. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02641-2 · Cited by 10 · see citing works
Mitsadali, I., Grayson, B., Idris, N. F., Watson, L., Burgess, M. A., & Neill, J. C. (2020) · Journal of Psychopharmacology · doi:10.1177/0269881120922963 · Cited by 10 · see citing works
“Email: Joanna.neill@manchester.ac.uk, www.b-neuro.com 67 (GAD67; Chung et al., 2016; Curley et al., 2011; Konradi et al., 2011).”
Cortical interneurons in schizophrenia – cause or effect?
Prkačin, M. V., Banovac, I., Petanjek, Z., & Hladnik, A. (2023) · Croatian Medical Journal · doi:10.3325/cmj.2023.64.110 · Cited by 10 · see citing works
“…PV+ neurons (IHC) DLPFC subiculum entorhinal cortex inferior colliculus hippocampus Beasley and Reynolds 1997, Konradi et al 2011, Wang et al 2011, Chung et al 2016, Kilonzo et al 2020, Kalus et al 1997, Shepard et al 2019, Woo et al 1997 Calbindin inconclusive (IHC, ISH, RT-PCR) DLPFC temporal…”
MethodFournier, L. A., Phadke, R. A., Salgado, M., Brack, A., Nocon, J. C., Bolshakova, S., Grant, J. R., Padró-Luna, N. M., Sen, K., & Cruz‐Martín, A. (2024) · iScience · doi:10.1016/j.isci.2024.110800 · Cited by 9 · see citing works
“22 In support of this,dysregulatedErbB4,a receptoroftheSCZ-linkedproteinneuregulin-1,maycontributeto loweractivityofPVcellsbyreducing theirexcit-atory inputs.”
Tapias-Espinosa, C., Sánchez-González, A., Cañete, T., Sampedro-Viana, D., Castillo-Ruiz, M. D. M., Oliveras, I., Tobeña, A., Aznar, S., & Fernández‐Teruel, A. (2022) · Behavioural Brain Research · doi:10.1016/j.bbr.2022.114113 · Cited by 9 · see citing works
Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia
Vinnakota, C., Hudson, M. R., Jones, N. C., Sundram, S., & Hill, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411835 · Cited by 7 · see citing works
Hur, K., Kim, S., Ma, S., Lee, B., Ko, Y., Seo, J., Kim, S., Kim, Y., Sung, S., Lee, Y., et al. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15528 · Cited by 9 · see citing works
“as a pathological basis for schizophrenia (Chung et al., 2016).”
BackgroundVarga, T. G., Simões, J. G. D. T., Siena, A., Henrique, E., da Silva, R. C. B., Bioni, V. S., Ramos, A. C., & Rosenstock, T. R. (2021) · Psychopharmacology · doi:10.1007/s00213-021-05880-1 · Cited by 9 · see citing works
Zhang, J., Zhou, H.-Q., Zhu, Z., Ding, Y.-Y., He, Y., Wei, X.-L., Xiao, C.-F., Li, Y., Lin, W.-P., & Yin, D. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150272 · Cited by 8 · see citing works
O'Brien, J. T., Jalilvand, S. P., Suji, N. A., Jupelly, R. K., Phensy, A. J., Mwirigi, J. M., Elahi, H., Price, T. J., & Kroener, S. (2024) · Schizophrenia Bulletin · doi:10.1093/schbul/sbae016 · Cited by 7 · see citing works
- 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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