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

Abstract

Arachidonoyldiacylglycerol (20:4-DAG) is a second messenger derived from phosphatidylinositol 4,5-bisphosphate and generated by stimulation of glutamate metabotropic receptors linked to G proteins and activation of phospholipase C. 20:4-DAG signaling is terminated by its phosphorylation to phosphatidic acid, catalyzed by diacylglycerol kinase (DGK). We have cloned the murine DGKε gene that showed, when expressed in COS-7 cells, selectivity for 20:4-DAG. The significance of DGKε in synaptic function was investigated in mice with targeted disruption of the DGKε. DGKε-/- mice showed a higher resistance to eletroconvulsive shock with shorter tonic seizures and faster recovery than DGKε+/+ mice. The phosphatidylinositol 4,5-bisphosphate-signaling pathway in cerebral cortex was greatly affected, leading to lower accumulation of 20:4-DAG and free 20:4. Also, long-term potentiation was attenuated in perforant path-dentate granular cell synapses. We propose that DGKε contributes to modulate neuronal signaling pathways linked to synaptic activity, neuronal plasticity, and epileptogenesis.