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Cited by 1,002Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.

Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics.

Akbarian, Schahram·1995·Archives of General Psychiatry
DOI 10.1001/archpsyc.1995.03950160008002
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Abstract

Background: Up-regulation of γ-aminobutyric acidA(GABAA) receptors and decreased GABA uptake in the cerebral cortex of schizophrenics suggest altered GABAergic transmission, which could be caused by primary disturbance of GABA synapses or by decreased production of the transmitter. Decreased production could be due to a shutdown in GABA production or to loss of GABA neurons caused by cell death or their failure to migrate to the cortex during brain development. Methods: To discriminate between these possibilities, we quantified levels of messenger RNA (mRNA) for the 67-kd isoform of glutamic acid decarboxylase (GAD), the key enzyme in GABA synthesis, and the number and laminar distribution of GAD mRNA-expressing neurons in the dorsolateral prefrontal cortex (DLPFC) of schizophrenics and matched controls, using in situ hybridization-histochemistry, densitometry, and cell-counting methods. These data were compared with the total number of neurons, the number of small, round or ovoid neurons 8 to 15 µm in diameter, and overall frontal lobe volume. As a control, mRNA levels for type II calciumcalmodulin-dependent protein kinase (CamIIK) were quantified. Results: Schizophrenics showed a pronounced decrease in GAD mRNA levels in neurons of layer I (40%) and layer II (48%) and an overall 30% decrease in layers III to VI. There were also strong overall reductions in GAD mRNA levels. The CamIIK mRNA levels showed no significant differences between samples. No differences were found in the total number of neurons nor in small, round or ovoid neurons, which should include a majority of the GABA cells. Prefrontal gray and white matter volume did not differ significantly between controls and schizophrenics. The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss. This may be brought about by an activitydependent down-regulation associated with the functional hypoactivity of the DLPFC. The lack of significant alterations in cell numbers in the DLPFC and frontal lobe volume in schizophrenics also implies that overall cortical neuronal migration had not been compromised in development. Previous reports of altered neuronal distribution in the subcortical white matter of schizophrenic brains in comparison with that of controls may indicate disturbances of migration or programmed cell death in the cortical subplate, leading to altered connection formation in the overlying cortex of schizophrenics and activity-dependent down-regulation of neurotransmitter-related gene expression. Conclusions: The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss. This may be brought about by an activity dependent down-regulation associated with the functional hypoactivity of the DLPFC. The lack of significant alterations in cell numbers in the DLPFC and frontal lobe volume in schizophrenics also implies that overall cortical neuronal migration had not been compromised in development. Previous reports of altered neuronal distribution in the subcortical white matter of schizophrenic brains in comparison with that of controls may indicate disturbances of migration or programmed cell death in the cortical subplate, leading to altered connection formation in the overlying cortex of schizophrenics and activity-dependent down-regulation of neurotrans mitter-related gene expression.

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Metadata

Authors
Akbarian, S.
Affiliations
University of California, Irvine (US)
Corresponding author
Akbarian, Schahram
ORCID
Akbarian, Schahram
Venue
Archives of General Psychiatry
Publisher
American Medical Association (AMA)
Published
1995-04-01
Volume
52
Issue
4
Pages
258
ISSN
0003-990X (ISSN-L)
DOI
10.1001/archpsyc.1995.03950160008002
OpenAlex
W2156026059
Cited by
1,002
References
49
Citations by year
2026: 8 · 2025: 8 · 2024: 15 · 2023: 12 · 2022: 15 · 2021: 22 · 2020: 32 · 2019: 36 · 2018: 19 · 2017: 32 · 2016: 38 · 2015: 51 · 2014: 49 · 2013: 43 · 2012: 47
FWCI
24.55
Type
journal article
Language
en
Open access
closed
Locations
  • Archives of General Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p50mh044188-05)
  • National Institute of Mental Health (MH44188)
  • National Institute of Neurological Disorders and Stroke (NS21377, R01NS021377)
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, GABA synthesis, dorsolateral prefrontal cortex, GABAergic neurotransmission, GABA receptors, GABA uptake, neuronal loss, cortical laminar distribution, neuronal migration, frontal lobe volume, gene expression, frontal lobe development
MeSH terms
Adult, Aged, Autoradiography, Cell Count, Densitometry, Female, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Humans, Male, Middle Aged, Neurons, RNA, Messenger, Schizophrenia, Down-Regulation, Gene Expression, Cell Death, Prefrontal Cortex, In Situ Hybridization, Age of Onset, Receptors, GABA

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