Isoform specific differences in phospholipase C beta 1 expression in the prefrontal cortex in schizophrenia and suicide

M Udawela,M Udawela,E Scarr,E Scarr,A J Hannan,J Y Um,B Dean,B Dean,B Dean,C C Felder,J Y Um,C Mcomish,C Mcomish,E A Thomas,S Boer,S Boer

doi:10.1038/s41537-017-0020-x

Abstract

Our previous study demonstrated that phospholipase C beta 1 mRNA was down-regulated in Brodmann’s area 46 from subjects with schizophrenia. However, phospholipase C beta 1 protein has also been shown to be lower in Brodmann’s area 8 and 9 from teenage suicide subjects, creating a potential confound in interpreting the findings in schizophrenia due to the high suicide rate associated with this disorder. To begin to reconcile and consolidate these findings, in this study, we measured mRNA and protein levels of phospholipase C beta 1 variants a and b in Brodmann’s area 46 and Brodmann’s area 9 from subjects with schizophrenia, many of whom were suicide completers, and determined the diagnostic specificity of observed findings. Consistent with our previous study, levels of phospholipase C beta 1 a and b mRNA, but not protein, were lower in Brodmann’s area 46 from subjects with schizophrenia. In Brodmann’s area 9, phospholipase C beta 1a protein levels were lower in subjects with schizophrenia, while phospholipase C beta 1b mRNA was higher and protein was lower in those that had died of suicide. Altered protein levels in Brodmann’s area 9 appeared to be diagnostically specific, as we did not detect these changes in subjects with bipolar disorder, major depressive disorder or suicide completers with no diagnosis of mental illness. We further assessed the relationship between phospholipase C beta 1 and levels of muscarinic receptors (CHRMs) that signal through this protein, in both human and Chrm knockout mouse central nervous system tissue, and found no strong relationship between the two. Understanding central nervous system differences in downstream effector pathways in schizophrenia may lead to improved treatment strategies and help to identify those at risk of suicide.

Highlights

Phospholipase C beta 1 (PLCB1) is a rate-limiting enzyme for downstream signalling of several neurotransmitter systems implicated in the pathophysiology of schizophrenia (Sz).Regulated by the Gq/11 family of GTP-binding proteins, PLCB1 facilitates signalling of dopamine via the D1 and D2 receptors,[1, 2] serotonin via the 5-HT2A and 2C receptors,[3, 4] glutamate via the group 1 metabotropic glutamate receptors[5, 6] and acetylcholine via muscarinic receptors CHRM1, 3 and 5.7 PLCB1 may represent a point of convergence for a number of pathways known to be affected in Sz.[8,9,10,11] In support of the argument that changes in PLCB1 could have a role in the pathophysiology, we,[12] and others,[13, 14] have reported differences in PLCB1 expression in the central nervous system (CNS) from subjects with Sz
Regulated by the Gq/11 family of GTP-binding proteins, Phospholipase C beta 1 (PLCB1) facilitates signalling of dopamine via the D1 and D2 receptors,[1, 2] serotonin via the 5-HT2A and 2C receptors,[3, 4] glutamate via the group 1 metabotropic glutamate receptors[5, 6] and acetylcholine via muscarinic receptors CHRM1, 3 and 5.7 PLCB1 may represent a point of convergence for a number of pathways known to be affected in Sz.[8,9,10,11]
We reported lower levels of PLCB1 mRNA in Sz in Brodmann’s area (BA) 46 of the dorsolateral prefrontal cortex (DLPFC),[12] a region largely implicated in cognitive deficits associated with the disorder

Summary

Introduction

Phospholipase C beta 1 (PLCB1) is a rate-limiting enzyme for downstream signalling of several neurotransmitter systems implicated in the pathophysiology of schizophrenia (Sz).Regulated by the Gq/11 family of GTP-binding proteins, PLCB1 facilitates signalling of dopamine via the D1 and D2 receptors,[1, 2] serotonin via the 5-HT2A and 2C receptors,[3, 4] glutamate via the group 1 metabotropic glutamate receptors[5, 6] and acetylcholine via muscarinic receptors CHRM1, 3 and 5.7 PLCB1 may represent a point of convergence for a number of pathways known to be affected in Sz.[8,9,10,11] In support of the argument that changes in PLCB1 could have a role in the pathophysiology, we,[12] and others,[13, 14] have reported differences in PLCB1 expression in the central nervous system (CNS) from subjects with Sz. Post-hoc tests revealed that the variance in PLCB1a mRNA was due to lower levels in tissue from both groups of subjects with Sz compared to control (p = 0.01 MRDS, p = 0.03 non-MRDS, vs control, Fig. 1i).

Results

Conclusion