Map2k7 haploinsufficiency induces brain imaging endophenotypes and behavioral phenotypes relevant to schizophrenia

Openshaw, R. , Thomson, D. M., Thompson, R., Penninger, J. M., Pratt, J. A., Morris, B. J. and Dawson, N. (2020) Map2k7 haploinsufficiency induces brain imaging endophenotypes and behavioral phenotypes relevant to schizophrenia. Schizophrenia Bulletin, 46(1), pp. 211-223. (doi: 10.1093/schbul/sbz044) (PMID:31219577) (PMCID:PMC6942167)

Abstract

c-Jun N-terminal kinase (JNK) signaling contributes to functional plasticity in the brain and cognition. Accumulating evidence implicates a role for MAP kinase kinase 7 (MAP2K7), a JNK activator encoded by the Map2k7 gene, and other JNK pathway components in schizophrenia (ScZ). Mice haploinsufficient for Map2k7 (Map2k7+/− mice) display ScZ-relevant cognitive deficits, although the mechanisms are unclear. Here we show that Map2k7+/− mice display translationally relevant alterations in brain function, including hippocampal and mesolimbic system hypermetabolism with a contrasting prefrontal cortex (PFC) hypometabolism, reminiscent of patients with ScZ. In addition Map2k7+/− mice show alterations in functional brain network connectivity paralleling those reported in early ScZ, including PFC and hippocampal hyperconnectivity and compromised mesolimbic system functional connectivity. We also show that although the cerebral metabolic response to ketamine is preserved, the response to dextroamphetamine (D-amphetamine) is significantly attenuated in Map2k7+/− mice, supporting monoamine neurotransmitter system dysfunction but not glutamate/NMDA receptor (NMDA-R) dysfunction as a consequence of Map2k7 haploinsufficiency. These effects are mirrored behaviorally with an attenuated impact of D-amphetamine on sensorimotor gating and locomotion, whereas similar deficits produced by ketamine are preserved, in Map2k7+/− mice. In addition, Map2k7+/− mice show a basal hyperactivity and sensorimotor gating deficit. Overall, these data suggest that Map2k7 modifies brain and monoamine neurotransmitter system function in a manner relevant to the positive and cognitive symptoms of ScZ.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Openshaw, Rebecca Louise and Pratt, Dr Judith and Morris, Professor Brian
• Authors: Openshaw, R., Thomson, D. M., Thompson, R., Penninger, J. M., Pratt, J. A., Morris, B. J., and Dawson, N.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Schizophrenia Bulletin
• Publisher: Oxford University Press
• ISSN: 0586-7614
• ISSN (Online): 1745-1701
• Published Online: 20 June 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Schizophrenia Bulletin 46(1): 211-223
• Publisher Policy: Reproduced under a Creative Commons license

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
63234	5	MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16	George Baillie	Medical Research Council (MRC)	MR/K501335/1	MVLS GRADUATE SCHOOL