Sensitivity to MK-801 in phospholipase C-β1 knockout mice reveals a specific NMDA receptor deficit.
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.
Gray
Laura
L
Howard Florey Institute, University of Melbourne, Victoria, Australia.
McOmish
Caitlin E
CE
Scarr
Elizabeth
E
Dean
Brian
B
Hannan
Anthony J
AJ
D000704:Analysis of Variance; D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000378:metabolism; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005838:Genotype; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006799:Housing, Animal; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010641:Phenotype; D054799:Phospholipase C beta / Q000172:deficiency* / Q000235:genetics; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000172:deficiency; D012559:Schizophrenia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D012565:Schizophrenic Psychology; D013239:Stereotyped Behavior / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse