"Altogether, these results confirm that physiological endocannabinoid-dependent control of GABAergic transmission depends on intact CB1 signaling in GABAergic interneurons and suggest that the endocannabinoid system does not influence GABAergic transmission during the development of KA-induced seizures," they concluded. "Therefore, direct modulation of glutamatergic transmission by CB1 receptors expressed on cortical glutamatergic neurons appears to be the major mechanism of endocannabinoid-mediated protection against KA-induced seizures."

Furthermore, the researchers' experiments established that endocannabinoid receptors were also present in the same glutamatergic neurons in areas of the hippocampus known to be central to seizure generation. The researchers wrote that this finding "represents a novel step in understanding the progression of acute excitotoxic seizures and the development of epileptic states."

And significantly, when the researchers used a targeted virus to knock out the CB1 gene for the endocannabinoid receptor specifically in the glutamatergic neurons of the hippocampus, the mice also showed strong worsening of chemically induced seizures in comparison to mice still expressing CB1.

"Altogether, these observations support a hypothetical scenario in which acute KA-induced excitotoxic seizures would activate the endocannabinoid system in respect to its ability to inhibit only 'harmful' glutamatergic transmission, but not 'protective' GABAergic release," concluded Lutz, Marsicano, and colleagues.

"In conclusion, our study reveals a mechanism through which the endocannabinoid system is able to provide on-demand protection against acute behavioral seizures. CB1 expression on hippocampal glutamatergic circuits accounts for this protection and mi
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
16-Aug-2006