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

Abstract

SUMMARYThe endocannabinoid system plays a central role in retrograde synaptic communication, and controls both glutamatergic and c-aminobutyric acid (GABA)ergic transmission via type 1 cannabinoid (CB1) receptor. Both in sclerotic human hippocampi and in the chronic phase of pilocarpineinduced 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 endocannabinoidmediated retrograde synaptic signaling should take into account the opposite change in CB1-receptor expression observed on glutamatergic versus GABAergic axon terminals.

Functional Reduction in Cannabinoid-Sensitive Heterotypic Inhibition of Dentate Basket Cells in Epilepsy: Impact on Network Rhythms

“…These findings are consistent with earlier reposts following electrically induced SE and subsequent epilepsy (Sun et al 2007). Moreover, CB 1 R-expressing interneurons and terminals are not reduced in epileptic rats (Magloczky et al 2010). Taken together, our histological and physiological data indicate that a GABA B R-mediated functional, rather than a structural, decrease in AC-IN synaptic inputs to FS-BCs underlies the persistent decrease in CB 1 R-sensitive synaptic inhibition of FS-BC in epileptic rats.…”

Cannabinoids and Epilepsy

“…CBDV potentiated the effects of phenobarbital, ethosuximide, and valproate in 2 seizure models [181]. These studies suggest that both Δ9-THC and CBD provide significant protection from seizures [147,[154][155][156][157][158][159][160][161][162][163][164][165][166]. GABA = γ-aminobutryic acid in preclinical animal trials, presenting potential targets for human studies.…”

“…By reducing CB 1 R expression on inhibitory terminals (and presumed DSI), this homoeostatic process may limit network disinhibtion and restrain elevated excitability during prolonged epileptiform activity. In sclerotic hippocampal tissue removed from 1) 2 months post pilocarpine-induced seizures in mice [163], and 2) human patients [164], levels of CB 1 Rs remained consistently elevated in interneuron axonal terminals (Fig. 3, light red trace).…”

CB2 Cannabinoid Receptors Promote Neural Progenitor Cell Proliferation via mTORC1 Signaling

“…The role of the eCB system in epileptogenesis and long term neural plasticity is relevant not only in animal models but perhaps also in the human epileptic brain (1). Thus, CB 1 receptors are regulated in a dynamic manner by synaptic activity and become down-regulated in the human epileptic hippocampus (47,48). However, the possible involvement of CB 2 receptors in these pathological events is still unknown.…”