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The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice

Boerner, T.; Bygrave, A.; Chen, J.; Fernando, A.; Jackson, S.; Barkus, C.; Sprengel, R.; Seeburg, P. H.; Harrison, P. J.; Gilmour, G.; Bannerman, D. M.; Sanderson, D. J.

The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice Thumbnail


Authors

T. Boerner

A. Bygrave

J. Chen

A. Fernando

S. Jackson

C. Barkus

R. Sprengel

P. H. Seeburg

P. J. Harrison

G. Gilmour

D. M. Bannerman



Abstract

Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1-/- mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1-/- mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.

Citation

Boerner, T., Bygrave, A., Chen, J., Fernando, A., Jackson, S., Barkus, C., …Sanderson, D. J. (2017). The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice. European Journal of Neuroscience, 45(7), 912-921. https://doi.org/10.1111/ejn.13539

Journal Article Type Article
Acceptance Date Feb 7, 2017
Online Publication Date Mar 4, 2017
Publication Date Apr 1, 2017
Deposit Date Feb 14, 2017
Publicly Available Date Mar 28, 2024
Journal European Journal of Neuroscience
Print ISSN 0953-816X
Electronic ISSN 1460-9568
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 45
Issue 7
Pages 912-921
DOI https://doi.org/10.1111/ejn.13539
Public URL https://durham-repository.worktribe.com/output/1394492

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Copyright Statement
© 2017 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproductionin any medium, provided the original work is properly cited.







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