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Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features.
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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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CSF GABA is reduced in first-episode psychosis and associates to symptom severity
Orhan, F., Fatouros‐Bergman, H., Goiny, M., Malmqvist, A., Piehl, F., Červenka, S., Collste, K., Victorsson, P. I., Sellgren, C. M., Flyckt, L., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.25 · Cited by 66
The Fragile Brain: Stress Vulnerability, Negative Affect and GABAergic Neurocircuits in Psychosis
Taylor, S. F., Grove, T. B., Ellingrod, V. L., & Tso, I. F. (2019) · Schizophrenia Bulletin · doi:10.1093/schbul/sbz046 · Cited by 67
Prefrontal Cortical GABA Modulation of Spatial Reference and Working Memory
Auger, M. L., & Floresco, S. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyu013 · Cited by 66
“mRNA and protein levels of the GABA synthesis enzyme glutamic acid decarboxylase-67 are consistently found to be reduced in the prefrontal cortex (PFC) of schizophrenics (Akbarian et al., 1995; Guidotti et al., 2000; Volk et al., 2000; Hashimoto et al., 2008; Thompson et al., 2009; Curley et al., 2011), potentially le…”
BackgroundMüller, I., Çalışkan, G., & Stork, O. (2014) · Genes Brain & Behavior · doi:10.1111/gbb.12188 · Cited by 67
Renard, J., Rushlow, W. J., & Laviolette, S. R. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00281 · Cited by 62
“A reduction of GAD 67 mRNA and protein levels is observed in layers 1 through 5 of post-mortem dorsolateral PFC brain tissue from patients with schizophrenia (23, 24, 45, 58, 59).”
MethodGeorgiev, D., Arion, D., Enwright, J. F., Kikuchi, M., Minabe, Y., Corradi, J. P., Lewis, D. A., & Hashimoto, T. (2014) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2013.13040468 · Cited by 61
“For example, in the prefrontal cortex of subjects with schizophrenia, parvalbumin neurons exhibit lower mRNA and protein levels of GAD67 (the 67-kDa isoform of glutamic acid decarboxylase, an enzyme for GABA synthesis) (5, 6), reduced immunoreactivity of GABA transporter 1 (a presynaptic GABA transporter) (7), and low…”
Self-citationMitchell, A., Jiang, Y., Peter, C. J., & Akbarian, S. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.10.020 · Cited by 65
“It has been suggested that approximately one out of three disease cases are affected by a more robust, perhaps more than > 30% downregulation in expression when compared to unaffected controls (Curley et al., 2011; Volk et al., 2012).”
BackgroundChiu, P. W., Lui, S. S. Y., Hung, K. S. Y., Chan, R. C. K., Chan, Q., Sham, P. C., Cheung, E. F. C., & Mak, H. K. (2017) · Schizophrenia Research · doi:10.1016/j.schres.2017.07.021 · Cited by 60
Hui, K. K., Takashima, N., Watanabe, A., Chater, T. E., Matsukawa, H., Nekooki-Machida, Y., Nilsson, P., Endo, R., Goda, Y., Saido, T. C., et al. (2019) · Science Advances · doi:10.1126/sciadv.aau8237 · Cited by 61
“Postmortem studies using brain samples from ASD (6) and SZ (7) patients have revealed alterations in glutamic acid decarboxylase (GAD65 and GAD67) expression, further implicating defective GABAergic signaling in pathogenesis.”
BackgroundMarkedly Lower Glutamic Acid Decarboxylase 67 Protein Levels in a Subset of Boutons in Schizophrenia
Rocco, B. R., Lewis, D. A., & Fish, K. N. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.07.022 · Cited by 61
“Although less wellstudied, the deficit in GAD67 mRNA has been reported to be accompanied by lower GAD67 protein levels (6, 7, 9).”
BackgroundResultInfluentialSelf-citationCortical GABA markers identify a molecular subtype of psychotic and bipolar disorders
Volk, D. W., Sampson, A. R., Zhang, Y. R., Edelson, J. R., & Lewis, D. A. (2016) · Psychological Medicine · doi:10.1017/s0033291716001446 · Cited by 54
“In addition, deficits in these GABA neuron-related mRNAs were not seen in all schizophrenia subjects relative to pair-matched unaffected comparison subjects (Curley et al. 2011; Volk et al. 2012).”
InfluentialSelf-citationPrenatal ontogeny as a susceptibility period for cortical GABA neuron disturbances in schizophrenia
Volk, D. W., & Lewis, D. A. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.06.008 · Cited by 56
“…GABAsynthesizing enzyme GAD67 have been replicated across multiple subject cohorts and do not appear to be attributable to antipsychotic medications (Akbarian et al., 1995; Guidotti et al., 2000; Volk et al., 2000; Vawter et al., 2002; Straub et al., 2007; Duncan et al., 2010; Curley et al., 2011).”
BackgroundResultInfluentialSelf-citationTurkheimer, F., Leech, R., Expert, P., Lord, L.-D., & Vernon, A. C. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.04.014 · Cited by 55
White matter neuron biology and neuropathology in schizophrenia
Duchatel, R. J., Weickert, C. S., & Tooney, P. A. (2019) · Schizophrenia · doi:10.1038/s41537-019-0078-8 · Cited by 61
Synchrony in schizophrenia: a window into circuit-level pathophysiology
Spellman, T., & Gordon, J. A. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.08.009 · Cited by 59
“Vierling-Claassen D, Siekmeier P, Stufflebeam S, Kopell N: Modeling GABA alterations in schizophrenia: a link between impaired inhibition and altered gamma and beta range auditory entrainment.”
InfluentialLanz, T. A., Joshi, J. J., Reinhart, V., Johnson, K., Grantham, L. E., & Volfson, D. (2015) · PLoS ONE · doi:10.1371/journal.pone.0121744 · Cited by 55
“Total RNA was prepared in a trizol-chloroform extraction from one set of sections, while protein was prepared in another set according to published methods [9].”
MethodGlausier, J. R., Kimoto, S., Fish, K. N., & Lewis, D. A. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.010 · Cited by 53
Self-citationMapping 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 53
Self-citationNew Drug Treatments for Schizophrenia: A Review of Approaches to Target Circuit Dysfunction
Howes, O. D., Dawkins, E., Lobo, M. C., Kaar, S. J., & Beck, K. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.05.014 · Cited by 53
Gilabert‐Juan, J., Bellés, M., Sáez-Ibáñez, A. R., Carceller, H., Zamarbide-Forés, S., Moltó, M. D., & Nácher, J. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.07.008 · Cited by 56
“…GABA and some genes implicated in its metabolism have been associated with schizophrenia (Straub et al., 2007; Zai et al., 2009), specially the 67- kDa isoform of glutamic acid decarboxylase (GAD67) (see Akbarian and Huang, 2006; Beneyto and Lewis, 2011; Curley et al., 2011 for review).”
BackgroundTsubomoto, M., Kawabata, R., Zhu, X., Minabe, Y., Chen, K., Lewis, D. A., & Hashimoto, T. (2018) · Cerebral Cortex · doi:10.1093/cercor/bhy227 · Cited by 54
“First, in our previous analyses, none of comorbid factors, such as the presence of substance abuse/dependence at the time of death, the use of antidepressants, benzodiazepine/anticonvulsant or antipsychotics at the time of death, and suicide as the cause of death, had a significant effect on the expression of PV, SST,…”
BackgroundSelf-citationCurley, A. A., Eggan, S. M., Lazarus, M. S., Huang, Z. J., Volk, D. W., & Lewis, D. A. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.10.018 · Cited by 51
“(Curley et al., 2011), suggesting that these mice appropriately recapitulate this aspect of the illness.”
BackgroundMethodResultInfluentialSelf-citationEarly-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants
Neuray, C., Maroofian, R., Scala, M., Sultan, T., Pai, G. S., Mojarrad, M., Khashab, H. Y. E., deHoll, L., Yue, W. W., Alsaif, H. S., et al. (2020) · Brain · doi:10.1093/brain/awaa178 · Cited by 51
“The severity of the Gad67 phenotype in animal models might suggest severe phenotypical manifestions in humans, yet there have been few reported families with GAD1 mutations (Lynex et al., 2004; Saito et al., 2010; Curley et al., 2011; Ruzicka et al., 2015; Magri et al., 2018).”
BackgroundAltered Markers of Cortical γ-Aminobutyric Acid Neuronal Activity in Schizophrenia
Kimoto, S., Zaki, M. M., Bazmi, H. H., & Lewis, D. A. (2015) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2015.0533 · Cited by 53
Self-citationCortical Opioid Markers in Schizophrenia and across Postnatal Development
Volk, D. W., Radchenkova, P., Er, W., Sengupta, E. J., & Lewis, D. A. (2011) · Cerebral Cortex · doi:10.1093/cercor/bhr202 · Cited by 51
Self-citationCannabis in Adolescence: Lasting Cognitive Alterations and Underlying Mechanisms
Scheyer, A. F., Laviolette, S. R., Pélissier‐Alicot, A., & Manzoni, O. J. (2022) · Cannabis and Cannabinoid Research · doi:10.1089/can.2022.0183 · Cited by 51
Neurobehavioral effects of long‐term maternal fructose intake in rat offspring
Erbaş, O., Erdoğan, M. A., Khalilnezhad, A., Gürkan, F. T., Yiğittürk, G., Meral, A., & Taşkıran, D. (2018) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2018.07.001 · Cited by 52
“Decreased expression of GAD67 has been reported in the brain of individuals with schizophrenia (Curley et al., 2011) and autism (Fatemi et al., 2002).”
BackgroundSohal, V. S. (2022) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20220147 · Cited by 51
Basta‐Kaim, A., Fijał, K., Ślusarczyk, J., Trojan, E., Głombik, K., Budziszewska, B., Leśkiewicz, M., Regulska, M., Kubera, M., Lasoń, W., et al. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.12.013 · Cited by 48
Volk, D. W. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.12.019 · Cited by 47
Self-citation
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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