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Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

Shortall, Sinead E.; Brown, Angus M.; Newton-Mann, Eliot; Dawe-Lane, Erin; Evans, Chanelle; Fowler, Maxine; King, Madeleine V.

Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia Thumbnail


Authors

Sinead E. Shortall

ANGUS BROWN A.M.BROWN@NOTTINGHAM.AC.UK
Associate Professor

Eliot Newton-Mann

Erin Dawe-Lane

Chanelle Evans

Maxine Fowler



Abstract

© 2020, The Author(s). Despite several compounds entering clinical trials for the negative and cognitive symptoms of schizophrenia, few have progressed beyond phase III. This is partly attributed to a need for improved preclinical models, to understand disease and enable predictive evaluation of novel therapeutics. To this end, one recent approach incorporates “dual-hit” neurodevelopmental insults like neonatal phencyclidine plus isolation rearing (PCP-Iso). Glutamatergic dysfunction contributes to schizophrenia pathophysiology and may represent a treatment target, so we used enzyme-based microsensors to evaluate basal- and drug-evoked glutamate release in hippocampal slices from rats that received neonatal PCP and/or isolation rearing. 5-HT6 antagonist-evoked glutamate release (thought to be mediated indirectly via GABAergic disinhibition) was reduced in PCP-Iso, as were cognitive effects of a 5-HT6 antagonist in a hippocampal glutamate-dependent novel object discrimination task. Yet mGlu7 antagonist-evoked glutamatergic and cognitive responses were spared. Immunohistochemical analyses suggest these findings (which mirror the apparent lack of clinical response to 5-HT6 antagonists in schizophrenia) are not due to reduced hippocampal 5-HT input in PCP-Iso, but may be explained by reduced calbindin expression. This calcium-binding protein is present in a subset of GABAergic interneurons receiving preferential 5-HT innervation and expressing 5-HT6 receptors. Its loss (in schizophrenia and PCP-Iso) would be expected to reduce interneuron firing and potentially prevent further 5-HT6 antagonist-mediated disinhibition, without impacting on responses of VIP-expressing interneurons to mGlu7 antagonism. This research highlights the importance of improved understanding for selection of appropriate preclinical models, especially where disease neurobiology impacts on cells mediating the effects of potential therapeutics.

Citation

Shortall, S. E., Brown, A. M., Newton-Mann, E., Dawe-Lane, E., Evans, C., Fowler, M., & King, M. V. (2020). Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia. Molecular Neurobiology, 57(9), 3439–3457. https://doi.org/10.1007/s12035-020-01938-x

Journal Article Type Article
Acceptance Date May 13, 2020
Online Publication Date Jun 12, 2020
Publication Date 2020-09
Deposit Date May 28, 2020
Publicly Available Date Mar 28, 2024
Journal Molecular Neurobiology
Print ISSN 0893-7648
Electronic ISSN 1559-1182
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 57
Issue 9
Pages 3439–3457
DOI https://doi.org/10.1007/s12035-020-01938-x
Keywords Neonatal PCP, Isolation rearing, Glutamate, 5-HT6, mGlu7, Calbindin
Public URL https://nottingham-repository.worktribe.com/output/4523314
Publisher URL https://link.springer.com/article/10.1007/s12035-020-01938-x
Additional Information Received: 21 February 2020; Accepted: 13 May 2020; First Online: 12 June 2020; : ; : The authors declare that they have no conflict of interest.; : All applicable international, national, and institutional guidelines for the care and use of animals were followed.

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