Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition

Bast, Tobias; Pezze, Marie; McGarrity, Stephanie

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