Abstract
BackgroundDiacylglycerol 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).Methodology/Principal FindingsDGKβ 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/SignificanceThese 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.
Highlights
Stimulation of cell surface Gq protein-coupled receptors by many extracellular stimuli such as growth factors, hormones, and neurotransmitters, activates phospholipase C and results in the production of diacylglycerol (DG) from inositol phospholipids [1]
When mice were exposed to the five objects for 6 min in training session (Figure 1D), in which WT and DGKb KO mice spent equal time on each objects (Figure 1E), there was no difference in the time spent in the novel object during retention session (Figure 1F)
WT and DGKb KO mice spent equal time on exploring two objects (Figure S1). These results suggest that DGKb KO mice showed attention-deficit behavior
Summary
Stimulation of cell surface Gq protein-coupled receptors by many extracellular stimuli such as growth factors, hormones, and neurotransmitters, activates phospholipase C and results in the production of diacylglycerol (DG) from inositol phospholipids [1]. DG directly binds to protein kinase C, activating this multifunctional enzyme [2]. DG is further converted to phosphatidic acid (PA), and PA in turn activates many other proteins, such as mammalian target of rapamycin and Raf-1 kinase [4]. Diacylglycerol kinase (DGK) is an enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. DGKb is one of the subtypes of the DGK family and regulates many intracellular signaling pathways in the central nervous system. We demonstrated that DGKb knockout (KO) mice showed various dysfunctions of higher brain function, such as cognitive impairment (with lower spine density), hyperactivity, reduced anxiety, and careless behavior. We conducted further tests on DGKb KO mice in order to investigate the function of DGKb in the central nervous system, especially in the pathophysiology of attention deficit hyperactivity disorder (ADHD)
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