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Diacylglycerol kinase ? knockout mice exhibit attention-deficit behavior and an abnormal response on methylphenidate-induced hyperactivity.

ABSTRACT:

Background

Diacylglycerol kinase (DGK) is an enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. DGK? is one of the subtypes of the DGK family and regulates many intracellular signaling pathways in the central nervous system. Previously, we demonstrated that DGK? knockout (KO) mice showed various dysfunctions of higher brain function, such as cognitive impairment (with lower spine density), hyperactivity, reduced anxiety, and careless behavior. In the present study, we conducted further tests on DGK? KO mice in order to investigate the function of DGK? in the central nervous system, especially in the pathophysiology of attention deficit hyperactivity disorder (ADHD).

Methodology/principal findings

DGK? KO mice showed attention-deficit behavior in the object-based attention test and it was ameliorated by methylphenidate (MPH, 30 mg/kg, i.p.). In the open field test, DGK? KO mice displayed a decreased response to the locomotor stimulating effects of MPH (30 mg/kg, i.p.), but showed a similar response to an N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801 (0.3 mg/kg, i.p.), when compared to WT mice. Examination of the phosphorylation of extracellular signal-regulated kinase (ERK), which is involved in regulation of locomotor activity, indicated that ERK1/2 activation induced by MPH treatment was defective in the striatum of DGK? KO mice.

Conclusions/significance

These findings suggest that DGK? KO mice showed attention-deficit and hyperactive phenotype, similar to ADHD. Furthermore, the hyporesponsiveness of DGK? KO mice to MPH was due to dysregulation of ERK phosphorylation, and that DGK? has a pivotal involvement in ERK regulation in the striatum.

SUBMITTER: Ishisaka M

PROVIDER: S-EPMC3349656 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Diacylglycerol kinase β knockout mice exhibit attention-deficit behavior and an abnormal response on methylphenidate-induced hyperactivity.

Ishisaka Mitsue M Kakefuda Kenichi K Oyagi Atsushi A Ono Yoko Y Tsuruma Kazuhiro K Shimazawa Masamitsu M Kitaichi Kiyoyuki K Hara Hideaki H

PloS one 20120510 5

<h4>Background</h4>Diacylglycerol kinase (DGK) is an enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. DGKβ is one of the subtypes of the DGK family and regulates many intracellular signaling pathways in the central nervous system. Previously, we demonstrated that DGKβ knockout (KO) mice showed various dysfunctions of higher brain function, such as cognitive impairment (with lower spine density), hyperactivity, reduced anxiety, and careless behavior. In the present study, w ...[more]

PMID: 22590645

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