Disruption of PLC-$beta;1-Mediated Signal Transduction in Mutant Mice Causes Age-Dependent Hippocampal Mossy Fiber Sprouting and Neurodegeneration

Böhm, Detlef; Schwegler, Herbert; Kotthaus, Lisa; Nayernia, Karim; Rickmann, Michael; Köhler, Michael; Rosenbusch, Joachim; Engel, Wolfgang; Flügge, Gabriele; Burfeind, Peter

doi:10.1006/mcne.2002.1199

Cited by 48 publications

(35 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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. Therefore, in this study we present our characterization of the phenotype of the PLC-b1 KO mice, including behavioral paradigms assessing endophenotypes representative of aspects of schizophrenia symptomatology, 30,31 under different environmental and pharmacological conditions.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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Phospholipase C-b1 (PLC-b1) is a rate-limiting enzyme implicated in postnatal-cortical development and neuronal plasticity. PLC-b1 transduces intracellular signals from specific muscarinic, glutamate and serotonin receptors, all of which have been implicated in the pathogenesis of schizophrenia. Here, we present data to show that PLC-b1 knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenialike symptoms in rodents. Importantly, the locomotor hyperactivity and sensorimotor gating deficits in PLC-b1 knockout mice are subject to beneficial modulation by environmental enrichment. Furthermore, clozapine but not haloperidol (atypical and typical antipsychotics, respectively) rescues the sensorimotor gating deficit in these animals, suggesting selective predictive validity. We also demonstrate a relationship between the beneficial effects of environmental enrichment and levels of M1/M4 muscarinic acetylcholine receptor binding in the neocortex and hippocampus. Thus we have demonstrated a novel mouse model, displaying disruption of multiple postsynaptic signals implicated in the pathogenesis of schizophrenia, a relevant behavioral phenotype and associated gene-environment interactions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…PLCb1 is expressed in the cerebral cortex and hippocampus, where the enzyme regulates neuronal activity (Kim et al, 1997;Böhm et al, 2002), and in the cardiovascular system (Ushio-Fukai et al, 1998;Mende et al, 1999;Arthur et al, 2001;Descorbeth and Anand-Srivastava, 2010). In vascular smooth muscle cells exposed to high glucose concentrations, Ga q and PLCb1 expression increases, resulting in higher intracellular Ca 21 .…”

Section: Plcb Isoforms Splice Variants and Functionmentioning

confidence: 99%

Structural Insights into Phospholipase C-β Function

Lyon

Tesmer

2013

Molecular Pharmacology

115

128

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Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. The production of these molecules promotes the release of intracellular calcium and activation of protein kinase C, which results in profound cellular changes. The PLCb subfamily is of particular interest given its prominent role in cardiovascular and neuronal signaling and its regulation by G protein-coupled receptors, as PLCb is the canonical downstream target of the heterotrimeric G protein Ga q . However, this is not the only mechanism regulating PLCb activity. Extensive structural and biochemical evidence has revealed regulatory roles for autoinhibitory elements within PLCb, Gbg, small molecular weight G proteins, and the lipid membrane itself. Such complex regulation highlights the central role that this enzyme plays in cell signaling. A better understanding of the molecular mechanisms underlying the control of its activity will greatly facilitate the search for selective small molecule modulators of PLCb.

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“…In addition, seizure activity in PLCβ-1 mutant mice is due to an enhancement of N-methyl-D-aspartic acid (NMDA)-evoked currents in CA1 pyramidal neurons (22), and these events cause an excessive increment of excitatory amino acid receptors, which can have a neurotoxic effect on distinct neuronal cell populations in the hippocampus (18). Therefore, the down-regulation of PLCβ-1 immunoreactivity in the pre-seizure SS gerbil may be correlated with impaired control of hyperexcitability of the epileptic hippocampus because the unique expression of PLCβ-1 in excitatory hippocampal neu-http : //bmbreports.org rons is closely related to the normal functioning of excitatory neuronal circuitry (1).…”

Section: Resultsmentioning

confidence: 99%

Altered PLCβ-1 expression in the gerbil hippocampal complex following spontaneous seizure

Lee

Oh²,

Chung³

et al. 2011

BMB Reports

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Although the phospholipase C (PLC)β-1 isoform is associated with spontaneous seizure and distinctively expressed in the telencephalon, the distribution of PLCβ-1 expression in the epileptic gerbil hippocampus remains controversial. Therefore, we determined whether PLCβ-1 is associated with spontaneous seizure in an animal model of genetic epilepsy. In the present study, PLCβ-1 immunoreactivity was down-regulated in seizure-sensitive (SS) gerbils more than in seizure-resistant (SR) gerbils. The expression of PLCβ-1 within calretinin (CR)-positive neurons was rarely detected within the dentate hilar region of SS gerbils. PLCβ-1 immunoreactivity in the hippocampus was significantly elevated as compared to that in pre-seizure SS gerbil 3 h post-ictal. These findings suggest that alterations in PLCβ-1 immunoreactivity in the SS gerbil hippocampus may be closely related to the epileptic state of the gerbil brain and transiently elevated PLCβ-1 protein levels following seizure episodes. Such alterations may be compensatory responses in the SS gerbil hippocampus. [BMB reports 2011; 44(9) : 566-571]

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Disruption of PLC-$beta;1-Mediated Signal Transduction in Mutant Mice Causes Age-Dependent Hippocampal Mossy Fiber Sprouting and Neurodegeneration

Cited by 48 publications

References 83 publications

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

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

Structural Insights into Phospholipase C-β Function

Altered PLCβ-1 expression in the gerbil hippocampal complex following spontaneous seizure

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