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PMID: 15205885 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S. Review

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

Psychopharmacology ·Vol. 174 ·No. 1 ·2004-06-00 ·Pages 143-50

Lewis DA, Volk DW, Hashimoto T

Abstract

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. 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. 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.

MeSH Terms
Animals GABA Agents/therapeutic use GABA Plasma Membrane Transport Proteins Glutamate Decarboxylase/metabolism Humans Immunohistochemistry/methods Isoenzymes/metabolism Membrane Transport Proteins/metabolism Memory Disorders/drug therapy,etiology Memory, Short-Term/drug effects Models, Neurological Neurons/drug effects,physiology Parvalbumins/metabolism Prefrontal Cortex/drug effects,metabolism Receptors, GABA/metabolism Schizophrenia/complications Signal Transduction/drug effects gamma-Aminobutyric Acid/metabolism
Chemicals
GABA Agents GABA Plasma Membrane Transport Proteins Isoenzymes Membrane Transport Proteins Parvalbumins Receptors, GABA gamma-Aminobutyric Acid Glutamate Decarboxylase glutamate decarboxylase 1
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Lewis David A
Department of Psychiatry, University of Pittsburgh, 3811 O'Hara Street, W1651 BST, Pittsburgh, PA 15213, USA. [email protected]
Volk David W
Hashimoto Takanori
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Article Info
Journal
Psychopharmacology
Abbr.
Psychopharmacology (Berl)
ISSN
0033-3158
DOI
10.1007/s00213-003-1673-x
Email
[email protected]
Published
2004-06-00
Epub
2003-00-09
Pages
143-50
Language
English
Region
Germany
NLM ID
7608025
Subset
IM
Grants
NIMH NIH HHS · MH43784 · United States
NIMH NIH HHS · MH45156 · United States
NIMH NIH HHS · MH51234 · United States
External Links
PubMed source DOI: 10.1007/s00213-003-1673-x View journal details
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