Cited by 264Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

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GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

Guidotti, Alessandro, Auta, James, Davis, John M., Dong, Erbo, Grayson, Dennis R., Veldic, Marin, Zhang, Xianquan, Costa, Erminio·2005·Psychopharmacology

DOI 10.1007/s00213-005-2212-8

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Abstract

Rationale Cortical gamma-aminobutyric acid (GABA)ergic neurons contribute to the orchestration of pyramidal neuron population firing as follows: (1) by releasing GABA on GABA(A) and GABA(B) receptors, (2) by releasing reelin in the proximity of integrin receptors located on cortical pyramidal neuron dendritic spines, and (3) through reelin contributing to the regulation of dendritic spine plasticity by modulating dendritic resident mRNA translation. In schizophrenia (SZ) and bipolar (BP) postmortem brains, the downregulation of mRNAs encoding glutamic acid decarboxylase 67 (GAD(67)) and reelin decreases the cognate proteins coexpressed in prefrontal cortex (PFC) GABAergic neurons. This finding has been replicated in several laboratories. Such downregulation suggests that the neuropil hypoplasticity found in the PFC of SZ and BP disorder patients may depend on a downregulation of GABAergic function, which is associated with a decrease in reelin secretion from GABAergic neuron axon terminals on dendrites, somata, or axon initial segments of pyramidal neurons. Indirectly, this GABAergic neuron downregulation may play a key role in the expression of positive and negative symptoms of SZ and BP disorders.Objectives The above described GABAergic dysfunction may be addressed by pharmacological interventions to treat SZ and BP disorders using specific benzodiazepines (BZs), which are devoid of intrinsic activity at GABA(A) receptors including alpha(1) subunits but that act as full positive allosteric modulators of GABA action at GABA(A) receptors containing alpha(2), alpha(3), or alpha(5) subunits. These drugs are expected to enhance GABAergic signal transduction without eliciting sedation, amnesia, and tolerance or dependence liabilities.Results and conclusions BZs, such as diazepam, although they are efficient in equilibrating GABA(A) receptor signal transduction in a manner beneficial in the treatment of positive and negative symptoms of SZ, may not be ideal drugs, because by mediating a full positive allosteric modulation of GABA(A) receptors containing the alpha(1) subunit, they contribute to sedation and to the development of tolerance after even a brief period of treatment. In contrast, other BZ-binding site ligands, such as 6-(2bromophenyl)-8-fluoro-4H-imidazo [1,5-a][1,4] benzodiazepine-3-carboxamide (imidazenil), which fail to allosterically and positively modulate the action of GABA at GABA(A) receptors with alpha(1) subunits but that selectively allosterically modulate cortical GABA(A) receptors containing alpha(5) subunits, contribute to the anxiolytic, antipanic, and anticonvulsant actions of these ligands without producing sedation, amnesia, or tolerance. Strong support for the use of imidazenil in psychosis emerges from experiments with reeler mice or with methionine-treated mice, which express a pronounced reelin and GAD(67) downregulation that is also operative in SZ and BP disorders. In mice that model SZ symptoms, imidazenil increases signal transduction at GABA(A) receptors containing alpha(5) subunits and contributes to the reduction of behavioral deficits without producing sedation or tolerance liability. Hence, we suggest that imidazenil may be considered a prototype for a new generation of positive allosteric modulators of GABA(A) receptors, which, either alone or in combination with neuroleptics, should be evaluated in GABAergic dysfunction operative in the treatment of SZ and BP disorders with psychosis.

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Authors: Guidotti, A., Auta, J., Davis, J. M., Dong, E., Grayson, D. R., Veldic, M., Zhang, X., & Costa, E.
Affiliations: University of Illinois Chicago (US)
Corresponding author: Costa, Erminio
ORCID: Guidotti, Alessandro
Auta, James
Davis, John M.
Dong, Erbo
Grayson, Dennis R.
Zhang, Xianquan
Venue: Psychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2005-04-28
Volume: 180
Issue: 2
Pages: 191-205
ISSN: 0033-3158 (ISSN-L)
1432-2072
DOI: 10.1007/s00213-005-2212-8
OpenAlex: W2072551779
Cited by: 262
References: 104
Citations by year: 2026: 1 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 2 · 2021: 4 · 2020: 11 · 2019: 7 · 2018: 12 · 2017: 10 · 2016: 11 · 2015: 16 · 2014: 22 · 2013: 13 · 2012: 10
FWCI: 2.92
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Psychopharmacology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Mental Health (R01MH6262A, R01MH062188, R01MH062090, R01MH62188, R01MH62090)
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, bipolar disorder, GABAergic dysfunction, GABAergic interneurons, reelin, GAD67, prefrontal cortex, benzodiazepines, positive allosteric modulation, GABAA receptor, alpha1 subunit, diazepam, sedation, drug tolerance, antipsychotic drugs, dendritic spine plasticity
MeSH terms: Reelin Protein, Animals, Benzodiazepines, Bipolar Disorder, Cerebral Cortex, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Humans, Nerve Tissue Proteins, Synaptic Transmission, Receptors, GABA-A, Schizophrenia, Serine Endopeptidases, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Chloride Channels

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GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

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