Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline

Openshaw, R. L. , Thomson, D.M., Penninger, J.M., Pratt, J.A. and Morris, B.J. (2017) Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline. Psychopharmacology, 234(2), pp. 293-305. (doi:10.1007/s00213-016-4463-y) (PMID:27774567) (PMCID:PMC5203862)

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Abstract

Rationale: Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. Objective: In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. Methods: Attentional function in mice haploinsufficient for Map2k7 (Map2k7+/− mice) was investigated using the five-choice serial reaction time task (5-CSRTT). Results: Once stable performance had been achieved, Map2k7+/− mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline—a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia—signs of improvement in attentional performance were detected. Conclusions: Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Thomson, Dr David and Morris, Professor Brian and Openshaw, Rebecca Louise
Authors: Openshaw, R. L., Thomson, D.M., Penninger, J.M., Pratt, J.A., and Morris, B.J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Psychopharmacology
Publisher:Springer
ISSN:0033-3158
ISSN (Online):1432-2072
Published Online:24 October 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Psychopharmacology 234(2):293-305
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
632341MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16Jeremy MottramMedical Research Council (MRC)MR/K501335/1III - PARASITOLOGY