Diacylglycerol Kinase Epsilon Modulates Rapid Kindling Epileptogenesis
- 24 February 2006
- Vol. 47 (2) , 267-276
- https://doi.org/10.1111/j.1528-1167.2006.00418.x
Abstract
Summary: Purpose:Diacylglycerol kinase epsilon (DGKε) regulates seizure susceptibility and long‐term potentiation through arachidonoyl‐inositol lipid signaling. We studied the significance of arachidonoyl‐diacylglycerol (20:4 DAG) in epileptogenesis in DGKε‐deficient mice undergoing rapid kindling epileptogenesis.Methods:Tripolar electrode units were implanted in right dorsal hippocampi of male DGKε+/+and DGKε−/−mice. Ten days after surgery, kindling was achieved by stimulating 6 times daily for 4 days with a subconvulsive electrical stimulation (10‐s train of 50‐Hz biphasic pulses, 75–200 μA amplitude) at 30‐min intervals. After 1 week, mice were rekindled. EEGs were recorded and analyzed to characterize epileptogenic events as spikes, sharp waves, or abnormal amplitudes and rhythms. Right hippocampi were analyzed by histology [Timm's staining, neuropeptide Y (NPY) and glial fibrillary acidic protein immunoreactivity], and for DNA fragmentation (TUNEL).Results:DGKε−/−mice had significantly fewer motor seizure and epileptic events compared with DGKε+/+mice from the second day of stimulation. These differences were maintained during rekindling. DGKε−/−mice also exhibited low‐amplitude spike–wave complexes, short spreading depression, and predominant lower‐frequency (1–4 Hz) bands throughout stimulation, whereas DGKε+/+mice exhibited increased high‐frequency bands (4–8 Hz; 8–15 Hz) from the second day of stimulation, as determined by power spectral analysis. DGKε−/−mice displayed no sprouting in the supragranular area or NPY inmunoreactivity in the hilus and had weak astrocyte reactivation in all hippocampal areas. No TUNEL‐positive cells were detected in any group of mice.Conclusions:DGKε modulates kindling epileptogenesis through inositol lipid signaling. Because arachidonate‐containing diacylglycerol phosphorylation to phosphatidic acid is selectively blocked in DGKε−/−mice, we postulate that the shortage of arachidonoyl‐moiety inositol lipids and/or the messengers derived thereof is a key signaling event in epileptogenesis.Keywords
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