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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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Increase in synaptic activity in granule cells from pilocarpine-treated mice that survived SE and developed TLE.A. sEPSCs recorded from granule cell of normal mouse. B. sEPSCs recorded from granule cell of a mouse that was injected with pilocarpine but did not develop SE. C. sEPSCs and bursting activity recorded from a granule cell of a pilocarpine-treated mouse that developed TLE. D. Trace showing that sEPSCs were blocked by application of ionotropic glutamate receptor antagonists, CNQX (10 µM) and AP-5 (50 µM). A1 and B1 are expanded boxed regions of A and B. C1, expansion of the sEPSC showing increased synaptic activity during the burst seen in C. Recordings were made in the absence of added Mg2+ and the presence of bicuculline (30 µM). E. Bar graph comparing the frequency of sEPSCs among the three groups of animals. Asterisk indicates significantly higher frequency in cells from mice with TLE (P<0.05).
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pone-0010683-g002: Increase in synaptic activity in granule cells from pilocarpine-treated mice that survived SE and developed TLE.A. sEPSCs recorded from granule cell of normal mouse. B. sEPSCs recorded from granule cell of a mouse that was injected with pilocarpine but did not develop SE. C. sEPSCs and bursting activity recorded from a granule cell of a pilocarpine-treated mouse that developed TLE. D. Trace showing that sEPSCs were blocked by application of ionotropic glutamate receptor antagonists, CNQX (10 µM) and AP-5 (50 µM). A1 and B1 are expanded boxed regions of A and B. C1, expansion of the sEPSC showing increased synaptic activity during the burst seen in C. Recordings were made in the absence of added Mg2+ and the presence of bicuculline (30 µM). E. Bar graph comparing the frequency of sEPSCs among the three groups of animals. Asterisk indicates significantly higher frequency in cells from mice with TLE (P<0.05).

Mentions: In nominally Mg2+-free ACSF that contained bicuculline (30 µM), a solution that was meant to expose multisynaptic glutamatergic connectivity and reduce recurrent GABAergic inhibition, patch-clamp recordings from granule cells in normal animals (n = 10) and in injected controls (n = 9) revealed sEPSCs with an average frequency of 1.45±0.17 Hz and 1.24±0.15 Hz, respectively (Fig. 2; P>0.05). In animals that had experienced SE and developed spontaneous seizures, barrages of sEPSCs were superimposed on the ongoing sEPSC activity (Fig. 2). The frequency of sEPSCs in cells from these animals, including those within the sEPSC barrages, was 3.03±0.28 Hz (n = 9), which was significantly higher than in either of the control groups (P<0.05). Within a given recording, these values varied little over time, but variability between cells could be large. Application of glutamate antagonists CNQX (10 µM) and AP5 (50 µM) blocked the sEPSCs and sEPSC barrages (n = 3; Fig 2).


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)

Increase in synaptic activity in granule cells from pilocarpine-treated mice that survived SE and developed TLE.A. sEPSCs recorded from granule cell of normal mouse. B. sEPSCs recorded from granule cell of a mouse that was injected with pilocarpine but did not develop SE. C. sEPSCs and bursting activity recorded from a granule cell of a pilocarpine-treated mouse that developed TLE. D. Trace showing that sEPSCs were blocked by application of ionotropic glutamate receptor antagonists, CNQX (10 µM) and AP-5 (50 µM). A1 and B1 are expanded boxed regions of A and B. C1, expansion of the sEPSC showing increased synaptic activity during the burst seen in C. Recordings were made in the absence of added Mg2+ and the presence of bicuculline (30 µM). E. Bar graph comparing the frequency of sEPSCs among the three groups of animals. Asterisk indicates significantly higher frequency in cells from mice with TLE (P<0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2871782&req=5

pone-0010683-g002: Increase in synaptic activity in granule cells from pilocarpine-treated mice that survived SE and developed TLE.A. sEPSCs recorded from granule cell of normal mouse. B. sEPSCs recorded from granule cell of a mouse that was injected with pilocarpine but did not develop SE. C. sEPSCs and bursting activity recorded from a granule cell of a pilocarpine-treated mouse that developed TLE. D. Trace showing that sEPSCs were blocked by application of ionotropic glutamate receptor antagonists, CNQX (10 µM) and AP-5 (50 µM). A1 and B1 are expanded boxed regions of A and B. C1, expansion of the sEPSC showing increased synaptic activity during the burst seen in C. Recordings were made in the absence of added Mg2+ and the presence of bicuculline (30 µM). E. Bar graph comparing the frequency of sEPSCs among the three groups of animals. Asterisk indicates significantly higher frequency in cells from mice with TLE (P<0.05).
Mentions: In nominally Mg2+-free ACSF that contained bicuculline (30 µM), a solution that was meant to expose multisynaptic glutamatergic connectivity and reduce recurrent GABAergic inhibition, patch-clamp recordings from granule cells in normal animals (n = 10) and in injected controls (n = 9) revealed sEPSCs with an average frequency of 1.45±0.17 Hz and 1.24±0.15 Hz, respectively (Fig. 2; P>0.05). In animals that had experienced SE and developed spontaneous seizures, barrages of sEPSCs were superimposed on the ongoing sEPSC activity (Fig. 2). The frequency of sEPSCs in cells from these animals, including those within the sEPSC barrages, was 3.03±0.28 Hz (n = 9), which was significantly higher than in either of the control groups (P<0.05). Within a given recording, these values varied little over time, but variability between cells could be large. Application of glutamate antagonists CNQX (10 µM) and AP5 (50 µM) blocked the sEPSCs and sEPSC barrages (n = 3; Fig 2).

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