Dopamine and the phosphorylated dopamine transporter are increased in the diacylglycerol kinase η-knockout mouse brain.

The molecular mechanisms generating the mania-like abnormal behaviors caused by diacylglycerol (DG) kinase (DGK) η deficiency remain unclear. Here, we found that DGKη knockout markedly increased dopamine (DA) levels in the midbrain (DA-producing region, 2.8-fold) and cerebral cortex (DA projection region, 1.2-fold). Moreover, DGKη deficiency significantly augmented phosphorylated DA transporter (DAT) levels (1.4-fold increase), which induce DA efflux to the synaptic cleft, in the cerebral cortex. Moreover, phosphorylation levels of protein kinase C-β, which is activated by DG and involved in DAT phosphorylation, were also increased. DAT expressed in Neuro-2a cells recruited DGKη to the plasma membrane and colocalized with it. These results strongly suggest that dopaminergic hyperfunction caused by DGKη deficiency in the brain leads to mania-like behaviors.