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Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition

Bast, Tobias; Pezze, Marie; McGarrity, Stephanie

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Authors

TOBIAS BAST tobias.bast@nottingham.ac.uk
Associate Professor

Marie Pezze

Stephanie McGarrity



Abstract

We review recent evidence concerning the significance of inhibitory GABA transmission and of neural disinhibition, i.e. deficient GABA transmission, within prefrontal cortex and hippocampus for clinically relevant cognitive functions. Both regions support important cognitive functions, including attention and memory, and their dysfunction has been implicated in cognitive deficits characterizing neuropsychiatric disorders. GABAergic inhibition shapes cortico-hippocampal neural activity and, recently, prefrontal and hippocampal neural disinhibition has emerged as a pathophysiological feature of major neuropsychiatric disorders, especially schizophrenia and age-related cognitive decline. Regional neural disinhibition, disrupting spatio-temporal control of neural activity and causing aberrant drive of projections, may disrupt processing within the disinhibited region and efferent regions. Recent studies in rats showed that prefrontal and hippocampal neural disinhibition (by local GABA antagonist microinfusion) dysregulates burst firing, which has been associated with important aspects of neural information processing. Using translational tests of clinically-relevant cognitive functions, these studies showed that prefrontal and hippocampal neural disinhibition disrupts regional cognitive functions (including prefrontal attention and hippocampal memory function); moreover, hippocampal neural disinhibition disrupted attentional performance, which does not require the hippocampus, but requires prefrontal-striatal circuits modulated by the hippocampus. However, some prefrontal and hippocampal functions (including inhibitory response control) are spared by regional disinhibition. We consider conceptual implications of these findings, regarding the distinct relationships of distinct cognitive functions to prefrontal and hippocampal GABA tone and neural activity. Moreover, the findings support that prefrontal and hippocampal neural disinhibition contributes to clinically relevant cognitive deficits, and we consider pharmacological strategies for ameliorating cognitive deficits by rebalancing disinhibition-induced aberrant neural activity.

Citation

Bast, T., Pezze, M., & McGarrity, S. (2017). Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition. British Journal of Pharmacology, 174(19), 3211-3225. https://doi.org/10.1111/bph.13850

Journal Article Type Article
Acceptance Date May 3, 2017
Online Publication Date May 6, 2017
Publication Date Oct 1, 2017
Deposit Date May 9, 2017
Publicly Available Date May 9, 2017
Journal British Journal of Pharmacology
Print ISSN 0007-1188
Electronic ISSN 1476-5381
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 174
Issue 19
Pages 3211-3225
DOI https://doi.org/10.1111/bph.13850
Public URL https://nottingham-repository.worktribe.com/output/965938
Publisher URL http://onlinelibrary.wiley.com/doi/10.1111/bph.13850/full
Additional Information This is the peer reviewed version of the following article: Bast, T., Pezze, M., and McGarrity, S. (2017) Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition. British Journal of Pharmacology, which has been published in final form at http://dx.doi.org/10.1111/bph.13850. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Contract Date May 9, 2017