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Cited by 253Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction

Lewis, DavidA., Volk, DavidW., Hashimoto, Takanori·2004·Psychopharmacology
DOI 10.1007/s00213-003-1673-x
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Abstract

Rationale Disturbances in critical cognitive processes, such as working memory, are now regarded as core features of schizophrenia, but available pharmacological treatments produce little or no improvement in these cognitive deficits. Although other explanations are possible, these cognitive deficits appear to reflect a disturbance in executive control, the processes that facilitate complex information processing and behavior and that include context representation and maintenance, functions dependent on the dorsolateral prefrontal cortex (DLPFC). Studies in non-human primates indicate that normal working memory function depends upon appropriate GABA neurotransmission in the DLPFC, and alterations in markers of GABA neurotransmission are well documented in the DLPFC of subjects with schizophrenia.Objectives Thus, the purpose of this paper is to review the nature of the altered GABA neurotransmission in the DLPFC in schizophrenia, and to consider how these findings might inform the search for new treatments for cognitive dysfunction in this illness.Results and conclusions Postmortem studies suggest that markers of reduced GABA neurotransmission in schizophrenia may be selective for, or at least particularly prominent in, the subclass of GABA neurons, chandelier cells, that provide inhibitory input to the axon initial segment of populations of pyramidal neurons. Given the critical role that chandelier cells play in synchronizing the activity of pyramidal neurons, the pharmacological amelioration of this deficit may be particularly effective in normalizing the neural network activity required for working memory function. Because GABA(A) receptors containing the a(2) subunit are selectively localized to the axon initial segment of pyramidal cells, and appear to be markedly up-regulated in schizophrenia, treatment with novel benzodiazepine-like agents with selective activity at GABA(A) receptors containing the a(2) subunit may be effective adjuvant agents for improving working memory function in schizophrenia.

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  • Lewis et al. (2004) proposed that increasing inhibitory conductance onto pyramidal cells could be realized using activators of the alpha2 subunit of the GABAR, and an alpha2-subunit agonist was found to ameliorate working memory deficits induced by ketamine in monkeys.

    “Lewis et al. (2004) proposed that this could be realized using activators of the α2 subunit of the GABAR (which mediates perisomatic inhibition to the axon initial segment of pyramidal cells), and an α2-subunit agonist was found to ameliorate WM deficits induced by ketamine in monkeys (Castner et al. 2010).”

    From Linking microcircuit dysfunction to cognitive impairment: Effects of disinhibition associated with schizophrenia in a cortical working memory model (2014) · cites this paper as Lewis et al. 2004

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Authors
Lewis, D., Volk, D., & Hashimoto, T.
Affiliations
University of Pittsburgh (US)
ORCID
Hashimoto, Takanori
Venue
Psychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2003-12-09
Volume
174
Issue
1
Pages
143-50
ISSN
  • 0033-3158 (ISSN-L)
  • 1432-2072
DOI
10.1007/s00213-003-1673-x
OpenAlex
W2056372896
Cited by
253
References
95
Citations by year
2025: 1 · 2024: 8 · 2023: 3 · 2022: 5 · 2021: 12 · 2020: 6 · 2019: 5 · 2018: 8 · 2017: 12 · 2016: 9 · 2015: 17 · 2014: 15 · 2013: 15 · 2012: 11
FWCI
9.62
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Psychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Public Health Service
  • National Institute of Mental Health (MH43784, MH-51234, MH 45156, R01MH051234, P50MH045156)
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, working memory, dorsolateral prefrontal cortex, GABAergic neurotransmission, chandelier cells, axon initial segment, GABAA receptor, alpha2 subunit, cognitive impairment, executive function, postmortem brain
MeSH terms
Animals, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Humans, Immunohistochemistry, Isoenzymes, Memory Disorders, Memory, Short-Term, Models, Neurological, Neurons, Parvalbumins, Schizophrenia, Signal Transduction, Prefrontal Cortex, Receptors, GABA, GABA Agents, Membrane Transport Proteins, GABA Plasma Membrane Transport Proteins

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