Dynamic changes of CB1-receptor expression in hippocampi of epileptic mice and humans.

The endocannabinoid system plays a central role in retrograde synaptic communication, and controls both glutamatergic and gamma-aminobutyric acid (GABA)ergic transmission via type 1 cannabinoid (CB1) receptor. Both in sclerotic human hippocampi and in the chronic phase of pilocarpine-induced epilepsy in mice with sclerosis, CB1-receptor-positive interneuron somata were preserved both in the dentate gyrus and in the CA1 area, and the density of CB1-immunostained fibers increased considerably in the dentate molecular layer. This suggests that, although CB1 receptors are known to be reduced in density on glutamatergic axons, the CB1-receptor-expressing GABAergic axons sprout, or there is an increase of CB1-receptor levels on these fibers. The changes of CB1 immunostaining in association with the GABAergic inhibitory system appear to correlate with the severity of pyramidal cell loss in the CA1 subfield. These results confirm the involvement of the endocannabinoid system associated with GABAergic transmission in human temporal lobe epilepsy (TLE), as well as in the chronic phase of the pilocarpine model in mice. Pharmacotherapy aimed at the modulation of endocannabinoid-mediated retrograde synaptic signaling should take into account the opposite change in CB1-receptor expression observed on glutamatergic versus GABAergic axon terminals.