Cannabinoid-Mediated Inhibition of Recurrent Excitatory Circuitry in the Dentate Gyrus in a Mouse Model of Temporal Lobe Epilepsy

Abstract

Temporal lobe epilepsy (TLE) is a neurological condition associated with neuron loss, axon sprouting, and hippocampal sclerosis, which results in modified synaptic circuitry. Cannabinoids appear to be anti-convulsive in patients and animal models of TLE, but the mechanisms of this effect are not known. A pilocarpine-induced status epilepticus mouse model of TLE was used to study the effect of cannabinoid agonists on recurrent excitatory circuits of the dentate gyrus using electrophysiological recordings in hippocampal slices isolated from control mice and mice with TLE. Cannabinoid agonists WIN 55,212-2, anandamide (AEA), or 2-arachydonoylglycerol (2-AG) reduced the frequency of spontaneous and tetrodotoxin-resistant excitatory postsynaptic currents (EPSCs) in mice with TLE, but not in controls. WIN 55,212-2 also reduced the frequency of EPSCs evoked by glutamate-photolysis activation of other granule cells in epileptic mice. Secondary population discharges evoked after antidromic electrical stimulation of mossy fibers in the hilus were also attenuated by cannabinoid agonists. Agonist effects were blocked by the cannabinoid type 1 receptor (CB1R) antagonist AM251. No change in glutamate release was observed in slices from mice that did not undergo status epilepticus. Western blot analysis suggested an up-regulation of CB1R in the dentate gyrus of animals with TLE. These findings indicate that activation of CB1R present on nerve terminals can suppress recurrent excitation in the dentate gyrus of mice with TLE. This suggests a mechanism for the anti-convulsive role of cannabinoids aimed at modulating receptors on synaptic terminals expressed de novo after epileptogenesis.

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.…”

“…Levels of CB 1 R expression in the CA1-3 stratum oriens and radiatum (presumed excitatory inputs) and dentate gyrus steadily increased 1-week post-pilocarpine-induced seizures (Fig. 3, dark green trace) [147,[155][156][157][158]. However, sclerotic and nonsclerotic hippocampal tissue resected from patients with epilepsy displayed a reduction in DAGLα (2-AG biosynthetic enzyme), CB 1 R mRNA, and CB 1 R excitatory terminal immunoreactivity (Fig.…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…However, it remains unclear whether the increased TRPV1 expression described reflects an uninvolved and downstream consequence of disease or an integral part of the process. The preclinical literature describing TRPV1 involvement in epilepsy is conflicted where studies suggest no involvement [126,127], a proconvulsant effect, or an anticonvulsant effect of TRPV1 activation [128][129][130][131][132][133][134]. Overall, a larger number of studies suggest that the consequences of TRPV1 activation in epilepsy are detrimental which, given the large number of validated studies asserting overwhelmingly anticonvulsant effects of CBD in these animal models, suggests that TRPV1 activation by CBD is not part of its antiepileptic mechanism of action.…”

Increased neurogenesis after ACEA and levetiracetam treatment in mouse pilocarpine model of epilepsy

“…Mice were housed individually on a 12-hour day/night cycle at least 7 days prior to treatment with free access to food and tap water ad libitum. Pilocarpine study was performed in accordance to the procedure described by Bahaskaran and Smith [34] with minor changes. Mice were administered an i.p.…”