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Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features.
Open accessAbstract
OBJECTIVE: Cognitive deficits in schizophrenia are associated with altered activity of the dorsolateral prefrontal cortex, which has been attributed to lower expression of the 67 kDa isoform of glutamic acid decarboxylase (GAD67), the major γ-aminobutyric acid (GABA)-synthesizing enzyme. However, little is known about the relationship of prefrontal GAD67 mRNA levels and illness severity, translation of the transcript into protein, and protein levels in axon terminals, the key site of GABA production and function. METHOD: Quantitative polymerase chain reaction was used to measure GAD67 mRNA levels in postmortem specimens of dorsolateral prefrontal cortex from subjects with schizophrenia and matched comparison subjects with no known history of psychiatric or neurological disorders (N=42 pairs). In a subset of this cohort in which potential confounds of protein measures were controlled (N=19 pairs), Western blotting was used to quantify tissue levels of GAD67 protein in tissue. In five of these pairs, multilabel confocal immunofluorescence was used to quantify GAD67 protein levels in the axon terminals of parvalbumin-containing GABA neurons, which are known to have low levels of GAD67 mRNA in schizophrenia. RESULTS: GAD67 mRNA levels were significantly lower in schizophrenia subjects (by 15%), but transcript levels were not associated with predictors or measures of illness severity or chronicity. In schizophrenia subjects, GAD67 protein levels were significantly lower in total gray matter (by 10%) and in parvalbumin axon terminals (by 49%). CONCLUSIONS: The findings that lower GAD67 mRNA expression is common in schizophrenia, that it is not a consequence of having the illness, and that it leads to less translation of the protein, especially in the axon terminals of parvalbumin-containing neurons, support the hypothesis that lower GABA synthesis in parvalbumin neurons contributes to dorsolateral prefrontal cortex dysfunction and impaired cognition in schizophrenia.
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“Reduced PV and GAD67 protein levels are also seen in both prefrontal and temporal cortex of post-mortem brain tissues (Beasley and Reynolds, 1997; Curley et al., 2011; Glausier et al., 2014).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Curley et al., 2011
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“For example, in a recent study using a similar approach to assess glutamate decarboxylase 67 (GAD67) protein, a larger deficit was found within boutons than within total gray matter when both were assessed in the same subjects (51).”
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“The list of misexpressed genes in the cerebral cortex and other brain regions of individuals with schizophrenia includes transcripts involved in inhibitory or excitatory neurotransmission, myelination and metabolism, among others (Akbarian and Huang, 2009; Bauer et al., 2008; Connor and Akbarian, 2008; Curley et al.,…”
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Self-citationPositron emission tomography imaging of the γ-aminobutyric acid system
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“This hypothesis is based upon the observation that expression of the GABA synthesizing enzyme, GAD67, is reduced in PV-containing GABA neurons (Curley et al., 2011; Hashimoto et al., 2003; Volk et al., 2000) suggesting a reduction in cortical GABA synthesis in people with schizophrenia.”
Understanding human thiol dioxygenase enzymes: structure to function, and biology to pathology
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“Alternative splicing of this GAD1 gene results in two products, the predominant 67-kDa form and a less-frequent 25-kDa form (Curley et al. 2011).”
BackgroundGABA-Synthesizing Enzymes in Calbindin and Calretinin Neurons in Monkey Prefrontal Cortex
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Self-citationMaternal deprivation induces alterations in cognitive and cortical function in adulthood
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“In persons with schizophrenia, this transition does not fully occur, which may account for some of their inhibitory deficits after birth.([35,36])”
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“In schizophrenia, an upregulation in α 2 receptor subunits has been observed in the axon initial segment of pyramidal neurons, and a decrease in α 1 receptor subunits has been observed in layer 3 pyramidal neurons (Glausier and Lewis 2011; reviewed in Lewis 2014).”
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“Furthermore, this study reported reduced GAD67 staining within PV interneurons, which is consonant with findings in post-mortem studies investigating schizophrenia (Hashimoto et al., 2003b; Curley et al., 2011).”
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BackgroundLaminar Distribution of Subsets of GABAergic Axon Terminals in Human Prefrontal Cortex
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“Post-mortem studies have shown that there are lower levels of glutamate decarboxylase 67 (GAD67), the enzyme that synthesises GABA, across cortical regions in psychosis patients (Curley et al., 2011; Guidotti et al., 2000; Hashimoto et al., 2008; Volk et al., 2000).”
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BackgroundThe role of cannabinoid 1 receptor expressing interneurons in behavior
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“…using different techniques, Western blots and densitometry, that the proteins measured in this study are stable across PMIs reaching up to 20 h. Additionally, storage time showed little to no effect on their levels (Curley et al. 2011; Glausier et al. 2015; Moyer et al. 2012; Rocco et al. 2016a).”
InfluentialSelf-citationProlonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia
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ResultProfiles of VGF Peptides in the Rat Brain and Their Modulations after Phencyclidine Treatment
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BackgroundGlobal knockdown of glutamate decarboxylase 67 elicits emotional abnormality in mice
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“*P b 0.05, **P b 0.001 significantly different from VEH for that schizophrenia (Hashimoto et al., 2003; Curley et al., 2011).”
InfluentialGeorgiev, D. D., Yoshihara, T., Kawabata, R., Matsubara, T., Tsubomoto, M., Minabe, Y., Lewis, D. A., & Hashimoto, T. (2016) · Schizophrenia Bulletin · doi:10.1093/schbul/sbw022 · Cited by 23
“In the cerebral cortex of subjects with schizophrenia, the 67 kDa isoform of glutamic acid decarboxylase (GAD67), the enzyme principally responsible for cortical γ-amino butyric acid (GABA) synthesis, is markedly reduced in the subset of GABA neurons that express parvalbumin (PV), indicating altered GABA neurotransmis…”
BackgroundSelf-citationStem cell therapy: social recognition recovery in a FASD model
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“Some of the CFSE-labeled NSCs showed GAD67 positivity, the protein known to be involved in the axon terminals of PVinterneurons.11 In a previous study, we have investigated the peripherally injected cell migration and distribution in the brain by using double labeling with CFSE and [35S]-methionine.”
BackgroundMethodWearne, T. A., Parker, L. M., Franklin, J. L., Goodchild, A. K., & Cornish, J. L. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.08.038 · Cited by 21
Hughes, H., Brady, L. J., & Schoonover, K. E. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1440834 · Cited by 20
Xia, M., Wang, J., Sheng, J., Tang, Y., Li, C., Lim, K. O., He, B., Li, C., Xu, Y., & Wang, J. (2018) · Journal of Ect · doi:10.1097/yct.0000000000000507 · Cited by 20
Wang, T., Sinha, A. S., Akita, T., Yanagawa, Y., & Fukuda, A. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00284 · Cited by 19
“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…”
BackgroundMacDonald, M. L., Favo, D., Garver, M. E., Sun, Z., Arion, D., Ding, Y., Yates, N. A., Sweet, R. A., & Lewis, D. A. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0260-0 · Cited by 20
Self-citationMalt, E. A., Juhasz, K., Malt, U. F., & Naumann, T. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00059 · Cited by 21
“…suggest that compromised cortical PV+ interneuron function is a major hallmark of schizophrenia (Reynolds et al., 2004; Behrens and Sejnowski, 2009; Curley et al., 2011; Nullmeier et al., 2011; Nakazawa et al., 2012; Volk et al., 2012; Jiang et al., 2013; Glausier et al., 2014; Yanagi et al.,…”
BackgroundBeyond the γ-aminobutyric acid hypothesis of schizophrenia
Fujihara, K. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1161608 · Cited by 20
“Decreased GAD67 expression is particularly prominent in parvalbumin-positive cells (PV neurons) among the inhibitory interneurons (Hashimoto et al., 2003; Curley et al., 2011).”
BackgroundNa+, K+-ATPase α3 isoform in frontal cortex GABAergic neurons in psychiatric diseases
Hodes, A., Rosen, H., Ben-Ami, H. C., & Lichtstein, D. (2019) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2019.04.014 · Cited by 18
Uehara, T., Sumiyoshi, T., & Kurachi, M. (2015) · Current Neuropharmacology · doi:10.2174/1570159x13666151009120153 · Cited by 18
“In fact, levels of glutamate decarboxylase (GAD) 67, the enzyme that synthesizes GABA, mRNA and protein have been found consistently to be lower in the frontal cortex of subjects with schizophrenia [16-18].”
Lawn, T., Giacomel, A., Martins, D., Veronese, M., Howard, M. A., Turkheimer, F., & Dipasquale, O. (2024) · Communications Biology · doi:10.1038/s42003-024-06391-3 · Cited by 22
Sohal, V. S. (2023) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2023.102820 · Cited by 20
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 17
Self-citationBitanihirwe, B. K. Y., & Woo, T.-U. W. (2014) · Psychiatry Research · doi:10.1016/j.psychres.2014.09.016 · Cited by 16
“Likewise, the amount of GAD67 protein in PV basket cell terminals has also been shown to be decreased by as much as 50% (Curley et al., 2011).”
BackgroundInfluentialAuger, M. L., Meccia, J., & Floresco, S. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4670-1 · Cited by 16
Chromosomal Conformations and Epigenomic Regulation in Schizophrenia
Rajarajan, P., Jiang, Y., Kassim, B. S., & Akbarian, S. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.11.022 · Cited by 16
Riordan, A. J., Schaler, A. W., Fried, J., Paine, T. A., & Thornton, J. E. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.02.024 · Cited by 20
Fujihara, K., Sato, T., Miyasaka, Y., Mashimo, T., & Yanagawa, Y. (2020) · FEBS Open Bio · doi:10.1002/2211-5463.13065 · Cited by 15
Peselmann, N., Schmitt, A., Gebicke‐Haerter, P. J., & Zink, M. (2012) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-012-0367-y · Cited by 16
Alterations in Prefrontal Cortical Circuitry and Cognitive Dysfunction in Schizophrenia
Lewis, D. A., & Glausier, J. R. (2016) · Nebraska Symposium on Motivation/The Nebraska symposium on motivation · doi:10.1007/978-3-319-30596-7_3 · Cited by 15
Self-citationWearne, T. A., Parker, L. M., Franklin, J. L., Goodchild, A. K., & Cornish, J. L. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.03.018 · Cited by 15
Prefrontal cortical circuits in social behaviors: an overview
Cao, W., Li, H., & Luo, J. (2024) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2300743 · Cited by 14
“In SCZ, both messenger RNA (mRNA) and protein levels of 67 kDa glutamic acid decarboxylase (GAD67), the primary enzyme responsible for cortical GABA synthesis, are dimin ‐ ished in the PFC (Vawter et al., 2002; Woo et al., 2008; Curley et al., 2011; Kimoto et al., 2014).”
Rahman, T., Weickert, C. S., Harms, L. R., Meehan, C. L., Schall, U., Todd, J., Hodgson, D. M., Michie, P. T., & Purves-Tyson, T. D. (2020) · Scientific Reports · doi:10.1038/s41598-020-58449-x · Cited by 15
Auger, M. L., Meccia, J., Phillips, A. G., & Floresco, S. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107844 · Cited by 16
Detection of autoantibodies against GABAARα1 in patients with schizophrenia
Shiwaku, H., Nakano, Y., Kato, M., & Takahashi, H. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.10.007 · Cited by 14
Sokolenko, E., Nithianantharajah, J., & Jones, N. C. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108103 · Cited by 13
Cortical control of chandelier cells in neural codes
Jung, K., Choi, Y., & Kwon, H. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.992409 · Cited by 10
Zhou, F., & Roper, S. N. (2014) · Journal of Neurophysiology · doi:10.1152/jn.00126.2014 · Cited by 13
“Of note, impaired inhibition in different brain regions has been postulated to be a prominent contributor to both of these conditions (Curley et al. 2011; Rubenstein and Merzenich 2003).”
BackgroundAksić, M., Poleksić, J., Aleksić, D., Petronijević, N., Radonjić, N. V., Jakovcevski, M., Kapor, S., Divac, N., Filipović, B., & Jakovčevski, I. (2021) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2021.670766 · Cited by 13
“During cortical development, reelin is secreted from the Cajal–Retzius cells in the marginal zone and plays a critical role in controlling neuronal migration and layer formation in the neocortex and hippocampus (D’Arcangelo et al., 1995).”
BackgroundGABAergic Gene Regulatory Elements Used in Adeno-Associated Viral Vectors
Duba-Kiss, R., Niibori, Y., & Hampson, D. R. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.745159 · Cited by 14
“Dysfunction of PV-expressing GABAergic neurons have been implicated in several neurological and psychiatric disorders such as epilepsy (63, 64), autism (65– 67), and schizophrenia (30, 68, 69).”
BackgroundIzquierdo-Luengo, C., Ten-Blanco, M., Ponce-Renilla, M., Perezzan, R., Pereda-Pérez, I., & Berrendero, F. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02469-4 · Cited by 13
Wołoszynowska-Fraser, M. U., Wulff, P., & Riedel, G. (2017) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000360 · Cited by 13
“…reduction or absence of GAD67 mRNA in ~ 50% of parvalbumin-positive (PV+ ) GABAergic cells (Hashimoto et al., 2003; Gonzalez-Burgos et al., 2010; Curley et al., 2011), although there is no frank cell loss and the overall density of PV+ neurones in PFC is not different to that of healthy…”
BackgroundLaviolette, S. R. (2019) · Psychological Medicine · doi:10.1017/s0033291719003325 · Cited by 12
Stem cell therapy: a new approach to the treatment of refractory depression
Kigawa, Y., Hashimoto, E., Ukai, W., Ishii, T., Furuse, K., Tsujino, H., Shirasaka, T., & Saito, T. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1194-2 · Cited by 12
“Some of the CFSE-labeled NSCs showed GAD67 positivity, the protein known to be involved in the axon terminals of PV interneurons (Curley et al. 2011).”
BackgroundSoiffer, R. J., & Ritz, J. (1993) · PubMed · Cited by 12
Psychosis of Epilepsy: An Update on Clinical Classification and Mechanism
Qiu, Z., Guo, J., Chen, B., & Fang, J. (2025) · Biomolecules · doi:10.3390/biom15010056 · Cited by 14
“One study showed that patients with schizophrenia had lower mRNA and protein levels of glutamate decarboxylase (GAD) 67 [97], which is an enzyme that synthesizes GABA, compared with healthy individuals [98].”
l -Proline, GABA Synthesis and Gamma Oscillations in Schizophrenia
Volk, D. W., González‐Burgos, G., & Lewis, D. A. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.10.009 · Cited by 11
Self-citationShared co-expression networks in frontal cortex of the normal aged brain and schizophrenia
Kim, S., Jo, Y., Webster, M. J., & Lee, D. (2018) · Schizophrenia Research · doi:10.1016/j.schres.2018.09.010 · Cited by 12
Dowling, K. F., Dienel, S. J., Barile, Z. J., Bazmi, H. H., & Lewis, D. A. (2023) · Biological Psychiatry · doi:10.1016/j.biopsych.2023.04.003 · Cited by 11
Self-citationBassi, S., Seney, M. L., Argibay, P. F., & Sibille, E. L. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.02.006 · Cited by 13
“To reduce the within- and betweensubject measurement variance, samples were processed in matched pairs on the same gel four times, and results were replicated for a total of four different Western blots, with 16 replicates per pair (Curley et al., 2011).”
Metadata
- Authors
- Curley, A. A., Arion, D., Volk, D. W., Asafu-Adjei, J. K., Sampson, A. R., Fish, K. N., & Lewis, D. A.
- Affiliations
- University of Pittsburgh (US)
- Venue
- American Journal of Psychiatry
- Published
- 2011-09
- Volume
- 168
- Issue
- 9
- Pages
- 921-929
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC3273780
- OpenAlex
- W2159400463
- Cited by
- 283
- References
- 43
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 11 · 2023: 15 · 2022: 13 · 2021: 16 · 2020: 12 · 2019: 22 · 2018: 24 · 2017: 20 · 2016: 23 · 2015: 28 · 2014: 28 · 2013: 23 · 2012: 16
- FWCI
- 16.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- SK Life Science
- National Institutes of Health
- National Institute of Mental Health (P50MH084053, MH084053, R21MH085108, MH085108, R01MH043784, MH084016, K08MH084016, R37MH043784, 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 › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- schizophrenia, glutamic acid decarboxylase 67, GAD67, GABA synthesis, dorsolateral prefrontal cortex, parvalbumin neurons, axon terminals, GABAergic interneurons, cognitive impairment, postmortem brain
- MeSH terms
- Adult, Cognition Disorders, Female, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Humans, Male, Microscopy, Fluorescence, Middle Aged, Neurons, Parvalbumins, Reference Values, RNA, Messenger, Schizophrenia, Blotting, Western, Cohort Studies, Prefrontal Cortex, Presynaptic Terminals
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