Phospholipase C isozymes selectively couple to specific neurotransmitter receptors

Abstract

A variety of extracellular signals are transduced across the cell membrane by the enzyme phosphoinositide-specific phospholipase C-beta (PLC-beta) coupled with guanine-nucleotide-binding G proteins. There are four isoenzymes of PLC-beta, beta1-beta4, but their functions in vivo are not known. Here we investigate the role of PLC-beta1 and PLC-beta4 in the brain by generating null mutations in mice: we found that PLCbeta1-/- mice developed epilepsy and PLCbeta4-/- mice showed ataxia. We determined the molecular basis of these phenotypes and show that PLC-beta1 is involved in signal transduction in the cerebral cortex and hippocampus by coupling predominantly to the muscarinic acetylcholine receptor, whereas PLC-beta4 works through the metabotropic glutamate receptor in the cerebellum, illustrating how PLC-beta isoenzymes are used to generate different functions in the brain.

Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration

“…The specific regions assessed for [ 3 H]pirenzepine binding are of particular relevance as the behaviors disrupted in this mouse model hinge largely upon both hippocampal and neocortical functions. [45][46][47] In addition, PLC-b1 KO mice have been shown to have aberrant changes in the cortex and hippocampus during development and in the adult 3,9,[27][28][29]48 to which [ 3 H]pirenzepine binding deficits may now be added. While the binding of [ 3 H]pirenzepine is not specific to a single muscarinic receptor, the relative densities of muscarinic receptors in the cortex and hippocampus and the relative affinity of muscarinic receptors for [ 3 H]pirenzepine 37 would suggest that PLC-b1 KO mice have decreased muscarinic M1 receptors in the cortex and muscarinic M1/M4 receptors in the hippocampus.…”

“…Animals PLC-b1 KO mice 9 were bred from mice heterozygous for the null mutation on an SV129/C57Bl6 background strain. A preliminary behavioral screen established basic visual, oral and sensory abilities of the KO mice.…”

“…Genotype was determined by PCR. 3,9 At 4 weeks, PLC-b1 KO mice and littermate controls (wild-type or heterozygous mice) were weaned and housed in groups of 3-7, with food and water ad libitum. To improve their well-being, in addition to standard mouse chow, sunflower seeds were scattered throughout the cage, facilitating independent feeding for the smaller mice post-weaning and providing opportunity for foraging behaviors.…”

“…DAG can then stimulate protein kinase C, facilitating specific protein phosphorylation, while IP3 binds to its receptor which mobilizes intracellular stores of Ca 2 þ , an event known to be important for specific aspects of cortical development and plasticity. 7,8 PLC-b1 can therefore signal through multiple pathways that are known to respond to serotonergic, 9,10 dopaminergic, 11,12 cholinergic 9,13 or glutamatergic neurotransmission, 3,9 which have been implicated in the pathogenesis of schizophrenia.…”

“…[23][24][25] It is, therefore, significant that PLC-b1 represents a point of convergence for these signaling pathways and that levels of the protein have been shown to be altered in the cortex of chronic schizophrenic patients, increasing in the prefrontal cortex and decreasing in the superior temporal gyrus. 26 The outcomes of disrupted PLC-b1 signaling can be studied in PLC-b1 knockout (KO) mice, 9 which have been shown to have abnormal cortical maturation including aberrant barrel formation in the somatosensory cortex 3 as well as disrupted synapse formation and dendritic spine morphology. 27 Behaviorally, spatial memory deficits have been identified 28,29 but a more complete behavioral phenotype has not yet been established.…”