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Cannabinoid-mediated inhibition of recurrent excitatory circuitry in the dentate gyrus in a mouse model of temporal lobe epilepsy.

Bhaskaran MD, Smith BN - PLoS ONE (2010)

Bottom Line: Cannabinoids appear to be anti-convulsive in patients and animal models of TLE, but the mechanisms of this effect are not known.Agonist effects were blocked by the cannabinoid type 1 receptor (CB1R) antagonist AM251.This suggests a mechanism for the anti-convulsive role of cannabinoids aimed at modulating receptors on synaptic terminals expressed de novo after epileptogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky, United States of America.

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.

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Action potential dependence of epileptiform EPSC bursts.A. Spontaneous burst activity recorded from a granule cell in a pilocarpine-treated mouse that survived SE. B. The bursts were completely blocked by TTX (1 µM), indicating they were action potential-dependent. Action potential-independent mEPSCs were still seen in the presence of TTX. A1 and B1 are expanded segments of A and B respectively. The recordings were made in the absence of Mg2+ and presence of bicuculline (30 µM).
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pone-0010683-g003: Action potential dependence of epileptiform EPSC bursts.A. Spontaneous burst activity recorded from a granule cell in a pilocarpine-treated mouse that survived SE. B. The bursts were completely blocked by TTX (1 µM), indicating they were action potential-dependent. Action potential-independent mEPSCs were still seen in the presence of TTX. A1 and B1 are expanded segments of A and B respectively. The recordings were made in the absence of Mg2+ and presence of bicuculline (30 µM).

Mentions: Barrages of sEPSCs were also prevented by addition of TTX (1–2 µM; Fig. 3), which blocked action potential dependent synaptic release but did not prevent action potential-independent miniature EPSCs (mEPSCs), suggesting the barrages were due to action potentials in afferent neurons. We also determined whether action potential-independent glutamate release was different between the two groups. In the presence of TTX, mEPSC frequency in controls was 1.14±0.13 Hz (n = 14) and in pilocarpine-treated mice was 2.41±0.26 Hz (n = 18; P<0.05; unpaired t-test). These data suggested that granule cells from pilocarpine-treated mice that survived SE received enhanced spontaneous glutamatergic synaptic input versus control mice or mice that did not experience SE after pilocarpine injection. Activity of local glutamatergic neurons and of additional synaptic contacts contributed to the enhanced glutamate release.


Cannabinoid-mediated inhibition of recurrent excitatory circuitry in the dentate gyrus in a mouse model of temporal lobe epilepsy.

Bhaskaran MD, Smith BN - PLoS ONE (2010)

Action potential dependence of epileptiform EPSC bursts.A. Spontaneous burst activity recorded from a granule cell in a pilocarpine-treated mouse that survived SE. B. The bursts were completely blocked by TTX (1 µM), indicating they were action potential-dependent. Action potential-independent mEPSCs were still seen in the presence of TTX. A1 and B1 are expanded segments of A and B respectively. The recordings were made in the absence of Mg2+ and presence of bicuculline (30 µM).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2871782&req=5

pone-0010683-g003: Action potential dependence of epileptiform EPSC bursts.A. Spontaneous burst activity recorded from a granule cell in a pilocarpine-treated mouse that survived SE. B. The bursts were completely blocked by TTX (1 µM), indicating they were action potential-dependent. Action potential-independent mEPSCs were still seen in the presence of TTX. A1 and B1 are expanded segments of A and B respectively. The recordings were made in the absence of Mg2+ and presence of bicuculline (30 µM).
Mentions: Barrages of sEPSCs were also prevented by addition of TTX (1–2 µM; Fig. 3), which blocked action potential dependent synaptic release but did not prevent action potential-independent miniature EPSCs (mEPSCs), suggesting the barrages were due to action potentials in afferent neurons. We also determined whether action potential-independent glutamate release was different between the two groups. In the presence of TTX, mEPSC frequency in controls was 1.14±0.13 Hz (n = 14) and in pilocarpine-treated mice was 2.41±0.26 Hz (n = 18; P<0.05; unpaired t-test). These data suggested that granule cells from pilocarpine-treated mice that survived SE received enhanced spontaneous glutamatergic synaptic input versus control mice or mice that did not experience SE after pilocarpine injection. Activity of local glutamatergic neurons and of additional synaptic contacts contributed to the enhanced glutamate release.

Bottom Line: Cannabinoids appear to be anti-convulsive in patients and animal models of TLE, but the mechanisms of this effect are not known.Agonist effects were blocked by the cannabinoid type 1 receptor (CB1R) antagonist AM251.This suggests a mechanism for the anti-convulsive role of cannabinoids aimed at modulating receptors on synaptic terminals expressed de novo after epileptogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky, United States of America.

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.

Show MeSH
Related in: MedlinePlus