Diacylglycerol kinase ɛ regulates seizure susceptibility and long-term potentiation through arachidonoyl– inositol lipid signaling

^*Neuroscience Center of Excellence and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA 70112; and ^†The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 13, 2001 (received for review November 9, 2000)

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 DGKɛ gene that showed, when expressed in COS-7 cells, selectivity for 20:4-DAG. The significance of DGKɛ in synaptic function was investigated in mice with targeted disruption of the DGKɛ. DGKɛ^−/− mice showed a higher resistance to eletroconvulsive shock with shorter tonic seizures and faster recovery than DGKɛ^+/+ 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 DGKɛ contributes to modulate neuronal signaling pathways linked to synaptic activity, neuronal plasticity, and epileptogenesis.

Footnotes

↵ ‡ To whom reprint requests should be addressed. S.M.P., Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112; or N.G.B., Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112. E-mail: nbazan{at}lsuhsc.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

ECS,

electroconvulsive shock;

EPSP,

excitatory postsynaptic potential;

FFA,

free fatty acid;

HFS,

high-frequency stimulation;

LTP,

long-term potentiation;

mGluR,

metabotropic glutamate receptor;

PA,

phosphatidic acid;

PAF,

platelet-activating factor;

PIP2,

phosphatidylinositol 4,5-bisphosphate