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  • br Materials and methods br Results br Discussion


    Materials and methods
    Discussion To date, several reports have suggested an involvement of DGK in bipolar disorder. A splice variant at the COOH-terminus of DGKβ has been related to bipolar disorder [15] and DGKβ KO mice showed hyperactive behavior [17]. For the other DGK isoforms, a possible implication in bipolar disorder has been reported for DGKη, which is classified as type II DGK in bipolar disorder [19], [20]. In patients with bipolar disorder, increased DGKη mRNA levels and the presence of DGKη SNPs were reported [21], [22]. These reports suggest the DGKs themselves or peripheral signals of DGKs affect normal brain function. Indeed, peripheral signals of DGKs, such as glycogen synthase kinase-3 (GSK-3), the phosphoinositide pathway, and PKC are affected in bipolar disorder and have been suggested to be the therapeutic targets of mood-stabilizing drugs [23]. Thus, it is important to investigate the roles of DGKβ in the central nervous system to understand the pathology of bipolar disorder. Previously, we reported that abnormal behavior of DGKβ KO mice was ameliorated by treatment with lithium [17]. We also investigated the effect of haloperidol, which is one of the typical antipsychotics, and showed that haloperidol did not significantly decreased locomotor activity and abnormal anxiety levels [17]. In the present study, we used two drugs, valproate and olanzapine, and investigated their effect on the behavior of DGKβ KO mice. Valproate is among the most commonly used treatment for bipolar disorder mania (as is lithium), and its effect is well studied in animal models of mania [6], [24], [25]. The action mechanism is not well known but valproate showed a mood-stabilizing effect via stimulation of the synthesis of the neurotransmitter γ-aminobutyric acid (GABA). Olanzapine is one of the atypical antipsychotics and has been shown to affect the locomotor activity of hyperactive -mice [26]. It shows an anti-manic effect via increasing dopamine and melanotropin sale efflux [27]. Here, we evaluated locomotor activity and anxiety levels using the open-field test. Locomotor activity is assessed in various disease models such as those for schizophrenia, drug addiction, autism, and mania. Because the hyperactivity of DGKβ KO mice was ameliorated by treatment with lithium [17], we hypothesize that the hyperactivity of DGKβ KO mice is “mania-like behavior.” In the present study, chronic treatment with these two drugs ameliorated abnormal behavior, but not acute treatment. Chronic drug testing might be more real-life translational and appropriate since chronic dosing is also needed in bipolar disorder patients. That may be why acute treatments did not treat the mania-like profile. Indeed, chronic valproate previously also reduced hyperactivity in reduced DAT functioning mice and not in WT mice [6]. From these point, DGKβ KO mice would be possible to consider as the animal models of mania. However, not only affected olanzapine the behavior of DGKB KO mice, but also that of WT mice. It is well known that olanzapine and valproate affect the baseline behavior of WT mice [28]. These results suggest that olanzapine has some sedative effect, but that it is also effective in DGKβ KO mice. In this study, we did not investigate the mechanisms underlying the effect of olanzapine and valproate on the abnormal behaviors of DGKβ KO mice; however, the amelioration of the Akt-GSK3β signaling pathway might be involved. Previously, we reported that Akt-GSK3β signaling is impaired in the cortex of DGKβ KO mice and lithium treatment in DGKβ KO mice ameliorated not only mania-like behavior but also impaired Akt-GSK3β signaling [17]. Similar to lithium, various antipsychotics such as valproate and olanzapine have also been reported to affect Akt-GSK3β signaling [29], [30], [31]. In other animal models, the amelioration of Akt-GSK3β signaling has been suggested to attenuate abnormal behavior such as hyperactivity, anxiety, and cognitive function [32], [33], [34]. However, further studies are needed to clarify the mechanisms underlying the effect of valproate and olanzapine on the abnormal behavior of DGKβ KO mice.