Diacylglycerol kinase epsilon regulates seizure susceptibility and long-term potentiation through arachidonoylinositol lipid signaling

Arachidonoyldiacylglycerol (20:4-DAG) is a second messenger derived from ph osphatidylinositol 4,5-bisphosphate and generated by stimulation of glutama te metabotropic receptors linked to C proteins and activation of phospholip ase C. 20:4-DAG signaling is terminated by its phosphorylation to phosphati dic acid, catalyzed by diacylglycerol kinase (DGK). We have cloned the muri ne DGK epsilon gene that showed, when expressed in COS-7 cells, selectivity for 20:4-DAG. The significance of DGKe in synaptic function was investigat ed in mice with targeted disruption of the DGK epsilon. DCK epsilon (-/-) m ice showed a higher resistance to eletroconvulsive shock with shorter tonic seizures and faster recovery than DGK epsilon (+/+) mice. The phosphatidyl inositol 4,5-bisphosphate-signaling pathway in cerebral cortex was greatly affected, leading to lower accumulation of 20:4-DAG and free 20:4. Also, lo ng-term potentiation was attenuated in perforant path-dentate granular cell synapses. We propose that DGK epsilon contributes to modulate neuronal sig naling pathways linked to synaptic activity, neuronal plasticity, and epile ptogenesis.