Increased Seizure Susceptibility in a Mouse with Diacylglycerol Kinase &amp;lt;i&amp;gt;β&amp;lt;/i&amp;gt; Deficiency

Ishisaka, Mitsue; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Shirai, Yasuhito; Saito, Naoaki; Hara, Hideaki

doi:10.4236/nm.2013.42019

Cited by 7 publications

(9 citation statements)

References 26 publications

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“…These results suggest that DGKb plays an important role in synaptic formations, which is consistent with another study (59). In the hippocampal CA3 area of DGKb KO mice, the numbers of parvalbuminpositive interneurons decreased, which may contribute to the increment of seizure susceptibility toward kainic acid and pentylene tetrazol (55). In the cortex of DGKb KO mice, cortical spine density has been found to be significantly decreased and AktGSK3b signaling was impaired, which may be a strong contributor to manialike behavior such as hyperlocomotion, reduced anxiety, and reduced depres sion (32).…”

Section: Dgkbsupporting

confidence: 80%

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The Roles of Diacylglycerol Kinases in the Central Nervous System: Review of Genetic Studies in Mice

Ishisaka

Hara

2014

J Pharmacol Sci

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Abstract. Diacylglycerol kinase (DGK) is an enzyme that converts diacylglycerol to phosphatidic acid. To date, 10 isoforms of DGKs (a, b, g, d, e, z, h, q, i, and k) have been identified in mammals, and these DGKs show characteristic expression patterns and roles. The expression levels of DGKs are comparatively higher in the central nervous system than in other organs and may play several important roles in regulating higher brain functions. Currently, many studies have been performed to reveal the roles of DGKs by knocking down or overexpression of DGKs in vitro. Additionally, knockout or overexpression mice of several DGKs have been generated, and phenotypes of these mice have been studied. In this review, we discuss the roles of DGKs in the central nervous system based on recent findings in genetic models.

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Section: Dgkbsupporting

confidence: 80%

“…Based on their behavioral analysis, DGKb KO mice exhibit cognitive impairment, manialike behavior, and increased seizure susceptibility (25,32,55). DGKb has been reported to show unique membrane localization and its expression levels in rat brains rapidly increases after postnatal day 14 (56,57), when synaptic formation is progressing.…”

Section: Dgkbmentioning

confidence: 99%

The Roles of Diacylglycerol Kinases in the Central Nervous System: Review of Genetic Studies in Mice

Ishisaka

Hara

2014

J Pharmacol Sci

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“…Alterations in Dgkb , Dgkz , Dgke or Dgkk coincided with differences in lipid levels in various neuronal tissues . On the behavioral level, seizure susceptibility was enhanced by Dgkd knockdown and Dgkb knockout and reduced by Dgke loss . Dgkb −/− and Dgkh −/− male mice showed neurological phenotypes including hyperactivity and reduced depression, while Dgkk ‐deficient mice showed fragile X syndrome‐like social deficits and stereotypic behaviors .…”

Section: Introductionmentioning

confidence: 91%

“…[48][49][50][51][52][53][54][55] To determine the effect of Although there are variations in the total amount of time spent asleep ( Figure 6C), the average length of individual sleep bouts did not differ ( Figure 6D). However, the average wake bout was longer for dKO than WT mice throughout the light phase ( Figure 6E Dgkh -/- (14) WT (13) WT (15) Dgki -/- (16) WT (19) dKO (19) Figure 6F). Together, these data suggest that WT and dKO mice differ in the total proportion of time spent asleep because of differences in how long the mice stay awake between sleep bouts.…”

Section: Dko Females Have Disrupted Sleep Patternsmentioning

confidence: 99%

Mania‐ and anxiety‐like behavior and impaired maternal care in female diacylglycerol kinase eta and iota double knockout mice

Bartsch

Lord

Diering

et al. 2019

Genes Brain and Behavior

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Genome‐wide association studies linked diacylglycerol kinase eta and iota to mood disorders, including bipolar disorder and schizophrenia, and both genes are expressed throughout the brain. Here, we generated and behaviorally characterized female mice lacking Dgkh alone, Dgki alone, and double Dgkh/Dgki‐knockout (dKO) mice. We found that fewer than 30% of newborn pups raised by dKO females survived to weaning, while over 85% of pups survived to weaning when raised by wild‐type (WT) females. Poor survival under the care of dKO mothers was unrelated to pup genotype. Moreover, pups from dKO dams survived when fostered by WT dams, suggesting the poor survival rate of dKO‐raised litters was related to impaired maternal care by dKO dams. Nest building was similar between WT and dKO dams; however, some dKO females failed to retrieve any pups in a retrieval assay. Pups raised by dKO dams had smaller or absent milk spots and reduced weight, indicative of impaired nursing. Unlike WT females, postpartum dKO females showed erratic, panicked responses to cage disturbances. Virgin dKO females showed behavioral signs of anxiety and mania, which were not seen in mice lacking either Dgkh or Dgki alone. Our research indicates that combined deletion of Dgkh and Dgki impairs maternal behavior in the early postpartum period, and suggests female dKO mice model symptoms of mania and anxiety.

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“…Owing to the numerous roles of DAG, and the ten DGK isoforms in humans, few studies have considered a role for DGK-dependent signalling in disease states. The exceptions to this are several knockout studies that have linked various DGK isoforms with epilepsy [DGKβ ( Ishisaka et al, 2103 ), DGKδ ( Leach et al, 2007 ) and DGKε ( Rodriguez de Turco et al, 2001 )] and bipolar disorder [DGKβ ( Kakefuda et al, 2010 ; Squassina et al, 2009 ) and DGKη ( Baum et al, 2007 ; Moya et al, 2010 )]. In bipolar disorder, PKC levels are also elevated during manic episodes ( Friedman et al, 1993 ; Wang and Friedman, 1996 ), and lithium, a common bipolar disorder treatment, is known to increase DAG levels ( Brami et al, 1993 ; Drummond and Raeburn, 1984 ).…”

Section: Introductionmentioning

confidence: 99%

Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum

Kelly

Sharma

Wilkinson

et al. 2018

Disease Models &Amp; Mechanisms

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Valproic acid (VPA) provides a common treatment for both epilepsy and bipolar disorder; however, common cellular mechanisms relating to both disorders have yet to be proposed. Here, we explore the possibility of a diacylglycerol kinase (DGK) playing a role in regulating the effect of VPA relating to the treatment of both disorders, using the biomedical model Dictyostelium discoideum. DGK enzymes provide the first step in the phosphoinositide recycling pathway, implicated in seizure activity. They also regulate levels of diacylglycerol (DAG), thereby regulating the protein kinase C (PKC) activity that is linked to bipolar disorder-related signalling. Here, we show that ablation of the single Dictyostelium dgkA gene results in reduced sensitivity to the acute effects of VPA on cell behaviour. Loss of dgkA also provides reduced sensitivity to VPA in extended exposure during development. To differentiate a potential role for this DGKA-dependent mechanism in epilepsy and bipolar disorder treatment, we further show that the dgkA null mutant is resistant to the developmental effects of a range of structurally distinct branched medium-chain fatty acids with seizure control activity and to the bipolar disorder treatment lithium. Finally, we show that VPA, lithium and novel epilepsy treatments function through DAG regulation, and the presence of DGKA is necessary for compound-specific increases in DAG levels following treatment. Thus, these experiments suggest that, in Dictyostelium, loss of DGKA attenuates a common cellular effect of VPA relating to both epilepsy and bipolar disorder treatments, and that a range of new compounds with this effect should be investigated as alternative therapeutic agents.This article has an associated First Person interview with the first author of the paper.

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Increased Seizure Susceptibility in a Mouse with Diacylglycerol Kinase <i>β</i> Deficiency

Cited by 7 publications

References 26 publications

The Roles of Diacylglycerol Kinases in the Central Nervous System: Review of Genetic Studies in Mice

The Roles of Diacylglycerol Kinases in the Central Nervous System: Review of Genetic Studies in Mice

Mania‐ and anxiety‐like behavior and impaired maternal care in female diacylglycerol kinase eta and iota double knockout mice

Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum

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