CB1 Cannabinoid Receptors and On-Demand Defense Against Excitotoxicity

TLDR

High spiking activity can damage neurons, and signaling systems that protect against the consequences of abnormal discharge have been proposed. Conditional deletion of CB1 receptors from principal forebrain neurons, while sparing interneurons, caused kainic acid to induce excessive seizures in vivo. CB1-deficient mice exhibit a lowered threshold for kainic‑acid–induced excitation, fail to activate anandamide‑mediated protective mechanisms, and thus lack the endogenous cannabinoid system’s on‑demand defense against acute excitotoxicity.

Abstract

Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice,the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons.