gray-sensitivitytomk-2009.pdf (130.35 kB)
Sensitivity to MK-801 in phospholipase C-β1 knockout mice reveals a specific NMDA receptor deficit
journal contribution
posted on 2009-08-01, 00:00 authored by Laura GrayLaura Gray, C E McOmish, E Scarr, B Dean, A J HannanPhospholipase 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.
History
Journal
The international journal of neuropsychopharmacologyVolume
12Pagination
917 - 928Publisher
Oxford University PressLocation
Oxford, EnglandPublisher DOI
ISSN
1461-1457eISSN
1469-5111Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2009, Oxford University PressUsage metrics
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No categories selectedKeywords
Science & TechnologyLife Sciences & BiomedicineClinical NeurologyNeurosciencesPharmacology & PharmacyPsychiatryNeurosciences & NeurologyEnvironmental enrichmenthippocampusphospholipase C-beta 1psychotomimeticschizophreniaLONG-TERM DEPRESSIONSTRUCTURAL-CHANGESNEURONAL PATTERNSANTAGONISTCORTEXPLASTICITYDIFFERENTIATIONINVOLVEMENT
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