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Sensitivity to MK-801 in phospholipase C-β1 knockout mice reveals a specific NMDA receptor deficit

Gray, Laura, McOmish, Caitlin E., Scarr, Elizabeth, Dean, Brian and Hannan, Anthony J. 2009, Sensitivity to MK-801 in phospholipase C-β1 knockout mice reveals a specific NMDA receptor deficit, The international journal of neuropsychopharmacology, vol. 12, pp. 917-928, doi: 10.1017/S1461145709009961.

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Title Sensitivity to MK-801 in phospholipase C-β1 knockout mice reveals a specific NMDA receptor deficit
Author(s) Gray, Laura
McOmish, Caitlin E.
Scarr, Elizabeth
Dean, Brian
Hannan, Anthony J.
Journal name The international journal of neuropsychopharmacology
Volume number 12
Start page 917
End page 928
Total pages 12
Publisher Oxford University Press
Place of publication Oxford, England
Publication date 2009-08
ISSN 1461-1457
1469-5111
Summary Phospholipase C-β1 (PLC-β1) is a critical component of multiple signalling pathways downstream of neurotransmitter receptors. Mice lacking this enzyme display a striking behavioural phenotype with relevance to human psychiatric disease. Glutamatergic dysfunction is strongly associated with several abnormal behavioural states and may underlie part of the phenotype of the phospholipase C-β1 knockout (KO) mouse. A heightened response to glutamatergic psychotomimetic drugs is a critical psychosis-related endophenotype, and in this study it was employed as a correlate of glutamatergic dysfunction. Control (n=8) and PLC-β1 KO mice (n=6) were treated with MK-801, a NMDA receptor (NMDAR) antagonist, following either standard housing or environmental enrichment, and the motor function and locomotor activity thus evoked was assessed. In addition, MK-801 binding to the NMDAR was evaluated through radioligand autoradiography in post-mortem tissue (on a drug-naive cohort). We have demonstrated a significantly increased sensitivity to the effects of the NMDA antagonist MK-801 in the PLC-β1 KO mouse. In addition, we found that this mouse line displays reduced hippocampal NMDAR expression, as measured by radioligand binding. We previously documented a reversal of specific phenotypes in this mouse line following housing in an enriched environment. Enrichment did not alter this heightened MK-801 response, nor NMDAR expression, indicating that this therapeutic intervention works on specific pathways only. These findings demonstrate the critical role of the glutamatergic system in the phenotype of the PLC-β1 KO mouse and highlight the role of these interconnected signalling pathways in schizophrenia-like behavioural disruption. These results also shed further light on the capacity of environmental factors to modulate subsets of these phenotypes.
Language eng
DOI 10.1017/S1461145709009961
Field of Research 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2009, Oxford University Press
Persistent URL http://hdl.handle.net/10536/DRO/DU:30075520

Document type: Journal Article
Collection: School of Medicine
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