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GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia

Authors
  • Xu, Meng-yi1, 2
  • Wong, Albert H C3
  • 1 University of Toronto
  • 2 Centre for Addiction and Mental Health, Toronto, Ontario, Canada , Toronto (Canada)
  • 3 Pharmacology and the Institute of Medical Science, University of Toronto, and the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada , Toronto (Canada)
Type
Published Article
Journal
Acta Pharmacologica Sinica
Publisher
Springer Nature
Publication Date
Mar 22, 2018
Volume
39
Issue
5
Pages
733–753
Identifiers
DOI: 10.1038/aps.2017.172
Source
Springer Nature
Keywords
License
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Abstract

Schizophrenia is considered primarily as a cognitive disorder. However, functional outcomes in schizophrenia are limited by the lack of effective pharmacological and psychosocial interventions for cognitive impairment. GABA (gamma-aminobutyric acid) interneurons are the main inhibitory neurons in the central nervous system (CNS), and they play a critical role in a variety of pathophysiological processes including modulation of cortical and hippocampal neural circuitry and activity, cognitive function-related neural oscillations (eg, gamma oscillations) and information integration and processing. Dysfunctional GABA interneuron activity can disrupt the excitatory/inhibitory (E/I) balance in the cortex, which could represent a core pathophysiological mechanism underlying cognitive dysfunction in schizophrenia. Recent research suggests that selective modulation of the GABAergic system is a promising intervention for the treatment of schizophrenia-associated cognitive defects. In this review, we summarized evidence from postmortem and animal studies for abnormal GABAergic neurotransmission in schizophrenia, and how altered GABA interneurons could disrupt neuronal oscillations. Next, we systemically reviewed a variety of up-to-date subtype-selective agonists, antagonists, positive and negative allosteric modulators (including dual allosteric modulators) for α5/α3/α2 GABAA and GABAB receptors, and summarized their pro-cognitive effects in animal behavioral tests and clinical trials. Finally, we also discuss various representative histone deacetylases (HDAC) inhibitors that target GABA system through epigenetic modulations, GABA prodrug and presynaptic GABA transporter inhibitors. This review provides important information on current potential GABA-associated therapies and future insights for development of more effective treatments.

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