Diacylglycerol kinase epsilon modulates rapid kindling epileptogenesis.

Abstract

PURPOSE:

Diacylglycerol kinase epsilon (DGKepsilon) 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 DGKepsilon-deficient mice undergoing rapid kindling epileptogenesis.

METHODS:

Tripolar electrode units were implanted in right dorsal hippocampi of male DGKepsilon(+/+) and DGKepsilon(-/-) 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 muA 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:

DGKepsilon(-/-) mice had significantly fewer motor seizure and epileptic events compared with DGKepsilon(+/+) mice from the second day of stimulation. These differences were maintained during rekindling. DGKepsilon(-/-) mice also exhibited low-amplitude spike-wave complexes, short spreading depression, and predominant lower-frequency (1-4 Hz) bands throughout stimulation, whereas DGKepsilon(+/+) mice exhibited increased high-frequency bands (4-8 Hz; 8-15 Hz) from the second day of stimulation, as determined by power spectral analysis. DGKepsilon(-/-) 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:

DGKepsilon modulates kindling epileptogenesis through inositol lipid signaling. Because arachidonate-containing diacylglycerol phosphorylation to phosphatidic acid is selectively blocked in DGKepsilon(-/-) mice, we postulate that the shortage of arachidonoyl-moiety inositol lipids and/or the messengers derived thereof is a key signaling event in epileptogenesis.

• Authors: Alberto Musto, Nicolas G Bazan
• Journal: Epilepsia (Epilepsia) Vol. 47 Issue 2 Pg. 267-76 (Feb 2006) ISSN: 0013-9580 [Print] United States
• PMID: 16499750 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Phosphatidic Acids
• Inositol
• Diacylglycerol Kinase

Topics

• Animals
• Diacylglycerol Kinase (deficiency, metabolism, physiology)
• Disease Susceptibility (physiopathology)
• Electric Stimulation
• Electrodes, Implanted
• Electroencephalography
• Epilepsy (metabolism, physiopathology)
• Hippocampus (metabolism, physiopathology)
• Immunohistochemistry
• Inositol (physiology)
• Kindling, Neurologic (metabolism, physiology)
• Long-Term Potentiation (physiology)
• Male
• Mice
• Mice, Inbred BALB C
• Phosphatidic Acids (metabolism)
• Phosphorylation
• Signal Transduction (physiology)
• Synaptic Transmission (physiology)
• Time Factors