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

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.

Changes in levels of cortical metabotropic glutamate 2 receptors with gender and suicide but not psychiatric diagnoses

“…This study may also seems to be the first to report increased levels of GRM2 protein in BA 46 from suicide completers and extends the finding of an earlier finding showing higher levels of GRM2 expression in dorsolateral prefrontal cortex from MDD suicide completers (Gray et al, 2015). We have previously reported higher levels of serotonin 1D receptor (BA 9) (Dean et al, 2006) and mRNA encoding the glutamate ionotropic receptor NMDA type subunit 2β (BA 10) (Dean et al, 2016a) as well as lower levels of mu opioid receptor (BA 24) (Scarr et al, 2012), serotonin 2A receptors (BA 46) (Dean et al, 2014), phospholipase C beta 1a (BA 9) (Udawela et al, 2017) and mRNA encoding the glutamate ionotropic receptor NMDA type subunit 2β (BA 24) (Dean et al, 2016a) in suicide completers. Hence, our new findings on GRM2 adds to the to previous data to suggest there are complex changes the molecular architecture of the cortex of suicide completers, which in BA 46, may be particularly impacting on glutamatergic activity; a neurotransmitter that has been suggested to be affected in the CNS of suicide completers (Ernst et al, 2009;Sequeira et al, 2009).…”

Stimulation of phospholipase Cβ1 by Gαq promotes the assembly of stress granule proteins

“…(49)(50)(51)(52). Schizophrenia and suicide has been shown to specifically involve varying levels of PLCβ1a and 1b in the prefrontal cortex (51). It is also notable that the PLCβ1-associated proteins identified here play important roles in neuronal function.…”

“…It is notable that PLCβ1 is highly expressed in neuronal tissue (48) and reduced levels are associated with a host of neurological disorders that may result from disruptions in calcium signaling, neuronal cells proliferation and differentiation (e.g. (49)(50)(51)(52). Schizophrenia and suicide has been shown to specifically involve varying levels of PLCβ1a and 1b in the prefrontal cortex (51).…”

Stimulation of phospholipase Cβ1 by Gα q promotes the assembly of stress granule proteins

“…Note that reductions in the amount PLCβ1 are associated with a host of neurological disorders that may result from disruptions in Ca 2+ signaling and the proliferation and differentiation of neuronal cells ( 59 – 62 ). Schizophrenia and suicide specifically involve varying amounts of PLCβ1a and PLCβ1b in the prefrontal cortex ( 61 ). Note also that the PLCβ1-associated proteins identified here play important roles in neuronal function.…”