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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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Effect of cannabinoid agonists on TTX-independent mEPSCs in pilocarpine-treated mice that survived SE.A. mEPSCs recorded from a granule cell in the presence of TTX (1 µM). B. Trace showing the reduction of mEPSC frequency after application of AEA (10 µM). C. Wash to TTX alone (20 min) showing that the effect was reversible. A1, A2, B1, B2 and C1, C2 are expanded segments of A, B and C, respectively. Recordings were made in the presence of bicuculline (30 µM). D. Cumulative probability plot showing a change in the frequency of mEPSCs in this cell. E and F. Cumulative charts showing effect of AEA, WIN 55,212-2 and 2-AG on mEPSC frequency (E) and amplitude (F) on pilocarpine-treated (TLE) and control mice. Asterisk indicates significant change in mEPSC frequency (p<0.05); number of recordings shown in parentheses.
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pone-0010683-g005: Effect of cannabinoid agonists on TTX-independent mEPSCs in pilocarpine-treated mice that survived SE.A. mEPSCs recorded from a granule cell in the presence of TTX (1 µM). B. Trace showing the reduction of mEPSC frequency after application of AEA (10 µM). C. Wash to TTX alone (20 min) showing that the effect was reversible. A1, A2, B1, B2 and C1, C2 are expanded segments of A, B and C, respectively. Recordings were made in the presence of bicuculline (30 µM). D. Cumulative probability plot showing a change in the frequency of mEPSCs in this cell. E and F. Cumulative charts showing effect of AEA, WIN 55,212-2 and 2-AG on mEPSC frequency (E) and amplitude (F) on pilocarpine-treated (TLE) and control mice. Asterisk indicates significant change in mEPSC frequency (p<0.05); number of recordings shown in parentheses.

Mentions: To determine if the effect of CB agonists was due to binding of receptors on presynaptic terminals, we determined the effect of AEA on mEPSCs in the presence of TTX. In control animals, AEA did not change the frequency of mEPSCs (1.35±0.25 Hz control vs 1.25±0.17 Hz in AEA; n = 5; p>0.05). Application of AEA (10 µM) in pilocarpine treated mice that survived SE significantly reduced the frequency of mEPSCs from 2.53±0.40 Hz prior to drug application to 1.81±0.22 Hz after drug application (n = 15; P<0.05; Fig. 5). Within 10 min of application, the frequency of mEPSCs was decreased by AEA in 8 neurons and unchanged in three cells. In the remaining four cells, the frequency was transiently increased within the first 3 min of AEA application. The amplitude of mEPSCs was not affected by AEA in either group (P>0.05; Fig. 5F).


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)

Effect of cannabinoid agonists on TTX-independent mEPSCs in pilocarpine-treated mice that survived SE.A. mEPSCs recorded from a granule cell in the presence of TTX (1 µM). B. Trace showing the reduction of mEPSC frequency after application of AEA (10 µM). C. Wash to TTX alone (20 min) showing that the effect was reversible. A1, A2, B1, B2 and C1, C2 are expanded segments of A, B and C, respectively. Recordings were made in the presence of bicuculline (30 µM). D. Cumulative probability plot showing a change in the frequency of mEPSCs in this cell. E and F. Cumulative charts showing effect of AEA, WIN 55,212-2 and 2-AG on mEPSC frequency (E) and amplitude (F) on pilocarpine-treated (TLE) and control mice. Asterisk indicates significant change in mEPSC frequency (p<0.05); number of recordings shown in parentheses.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0010683-g005: Effect of cannabinoid agonists on TTX-independent mEPSCs in pilocarpine-treated mice that survived SE.A. mEPSCs recorded from a granule cell in the presence of TTX (1 µM). B. Trace showing the reduction of mEPSC frequency after application of AEA (10 µM). C. Wash to TTX alone (20 min) showing that the effect was reversible. A1, A2, B1, B2 and C1, C2 are expanded segments of A, B and C, respectively. Recordings were made in the presence of bicuculline (30 µM). D. Cumulative probability plot showing a change in the frequency of mEPSCs in this cell. E and F. Cumulative charts showing effect of AEA, WIN 55,212-2 and 2-AG on mEPSC frequency (E) and amplitude (F) on pilocarpine-treated (TLE) and control mice. Asterisk indicates significant change in mEPSC frequency (p<0.05); number of recordings shown in parentheses.
Mentions: To determine if the effect of CB agonists was due to binding of receptors on presynaptic terminals, we determined the effect of AEA on mEPSCs in the presence of TTX. In control animals, AEA did not change the frequency of mEPSCs (1.35±0.25 Hz control vs 1.25±0.17 Hz in AEA; n = 5; p>0.05). Application of AEA (10 µM) in pilocarpine treated mice that survived SE significantly reduced the frequency of mEPSCs from 2.53±0.40 Hz prior to drug application to 1.81±0.22 Hz after drug application (n = 15; P<0.05; Fig. 5). Within 10 min of application, the frequency of mEPSCs was decreased by AEA in 8 neurons and unchanged in three cells. In the remaining four cells, the frequency was transiently increased within the first 3 min of AEA application. The amplitude of mEPSCs was not affected by AEA in either group (P>0.05; Fig. 5F).

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