title: Diacylglycerol kinase β 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. 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, we conducted further tests on DGKβ KO mice in order to investigate the function of DGKβ in the central nervous system, especially in the pathophysiology of attention deficit hyperactivity disorder (ADHD).
  
  
  RESULTS
  DGKβ 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, DGKβ 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 DGKβ KO mice.
  
  
  CONCLUSIONS
  These findings suggest that DGKβ KO mice showed attention-deficit and hyperactive phenotype, similar to ADHD. Furthermore, the hyporesponsiveness of DGKβ KO mice to MPH was due to dysregulation of ERK phosphorylation, and that DGKβ has a pivotal involvement in ERK regulation in the striatum.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Mitsue
authors.initials: M
authors.lastname: Ishisaka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kakefuda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Oyagi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ono
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Kitaichi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D017109:Akathisia, Drug-Induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000494:pharmacology; D003342:Corpus Striatum / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019852:Diacylglycerol Kinase / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008774:Methylphenidate / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype
chemical_list: D000697:Central Nervous System Stimulants; D009419:Nerve Tissue Proteins; D008774:Methylphenidate; D019852:Diacylglycerol Kinase; D048052:Mitogen-Activated Protein Kinase 3