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GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

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Abstract

Rationale

Cortical γ-aminobutyric acid (GABA)ergic neurons contribute to the orchestration of pyramidal neuron population firing as follows: (1) by releasing GABA on GABAA and GABAB 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 (GAD67) 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 GABAA receptors including α1 subunits but that act as full positive allosteric modulators of GABA action at GABAA receptors containing α2, α3, or α5 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 GABAA 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 GABAA receptors containing the α1 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 GABAA receptors with α1 subunits but that selectively allosterically modulate cortical GABAA receptors containing α5 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 GAD67 downregulation that is also operative in SZ and BP disorders. In mice that model SZ symptoms, imidazenil increases signal transduction at GABAA receptors containing α5 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 GABAA 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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Acknowledgements

This work is supported by RO1MH62188 to A.G., RO1MH62090 to E.C., and RO1MH6262A to D.R.G.

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  1. Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor St, Chicago, IL, 60612, USA

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

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  1. Alessandro Guidotti
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  2. James Auta
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Correspondence to Erminio Costa.

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This work is dedicated to Professor Joseph A. Flaherty on the occasion of his promotion to Dean of the UIC College of Medicine.

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Guidotti, A., Auta, J., Davis, J.M. et al. GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon. Psychopharmacology 180, 191–205 (2005). https://doi.org/10.1007/s00213-005-2212-8

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