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Research Articles, Systems/Circuits

2-AG-Mediated Control of GABAergic Signaling Is Impaired in a Model of Epilepsy

Roberto Colangeli, Maria Morena, Allison Werner, Roger J. Thompson, Mario van der Stelt, Quentin J. Pittman, Matthew N. Hill and G. Campbell Teskey
Journal of Neuroscience 25 January 2023, 43 (4) 571-583; DOI: https://doi.org/10.1523/JNEUROSCI.0541-22.2022
Roberto Colangeli
1Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N4N1, Canada
2Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy
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Maria Morena
1Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N4N1, Canada
3Department of Physiology and Pharmacolgy, Sapienza University of Rome, 00185 Rome, Italy
4Neuropsychopharmacology Unit, Santa Lucia Foundation, 00143 Rome, Italy
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Allison Werner
1Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N4N1, Canada
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Roger J. Thompson
1Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N4N1, Canada
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Mario van der Stelt
5Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, 2333 CC, Leiden, The Netherlands
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Quentin J. Pittman
6Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1, Canada
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Matthew N. Hill
1Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N4N1, Canada
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G. Campbell Teskey
1Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N4N1, Canada
6Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N4N1, Canada
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Abstract

Repeated seizures result in a persistent maladaptation of endocannabinoid (eCB) signaling, mediated part by anandamide signaling deficiency in the basolateral amygdala (BLA) that manifests as aberrant synaptic function and altered emotional behavior. Here, we determined the effect of repeated seizures (kindling) on 2-arachidonoylglycerol (2-AG) signaling on GABA transmission by directly measuring tonic and phasic eCB-mediated retrograde signaling in an in vitro BLA slice preparation from male rats. We report that both activity-dependent and muscarinic acetylcholine receptor (mAChR)-mediated depression of GABA synaptic transmission was reduced following repeated seizure activity. These effects were recapitulated in sham rats by preincubating slices with the 2-AG synthesizing enzyme inhibitor DO34. Conversely, preincubating slices with the 2-AG degrading enzyme inhibitor KML29 rescued activity-dependent 2-AG signaling, but not mAChR-mediated synaptic depression, over GABA transmission in kindled rats. These effects were not attributable to a change in cannabinoid type 1 (CB1) receptor sensitivity or altered 2-AG tonic signaling since the application of the highly selective CB1 receptor agonist CP55,940 provoked a similar reduction in GABA synaptic activity in both sham and kindled rats, while no effect of either DO34 or of the CB1 inverse agonist AM251 was observed on frequency and amplitude of spontaneous IPSCs in either sham or kindled rats. Collectively, these data provide evidence that repeated amygdala seizures persistently alter phasic 2-AG-mediated retrograde signaling at BLA GABAergic synapses, probably by impairing stimulus-dependent 2-AG synthesis/release, which contributes to the enduring aberrant synaptic plasticity associated with seizure activity.

SIGNIFICANCE STATEMENT The plastic reorganization of endocannabinoid (eCB) signaling after seizures and during epileptogenesis may contribute to the negative neurobiological consequences associated with seizure activity. Therefore, a deeper understanding of the molecular basis underlying the pathologic long-term eCB signaling remodeling following seizure activity will be crucial to the development of novel therapies for epilepsy that not only target seizure activity, but, most importantly, the epileptogenesis and the comorbid conditions associated with epilepsy.

  • electrophysiology
  • endocannabinoids
  • epilepsy
  • GABA
  • kindling
  • synaptic plasticity

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The Journal of Neuroscience: 43 (4)
Journal of Neuroscience
Vol. 43, Issue 4
25 Jan 2023
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2-AG-Mediated Control of GABAergic Signaling Is Impaired in a Model of Epilepsy
Roberto Colangeli, Maria Morena, Allison Werner, Roger J. Thompson, Mario van der Stelt, Quentin J. Pittman, Matthew N. Hill, G. Campbell Teskey
Journal of Neuroscience 25 January 2023, 43 (4) 571-583; DOI: 10.1523/JNEUROSCI.0541-22.2022

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2-AG-Mediated Control of GABAergic Signaling Is Impaired in a Model of Epilepsy
Roberto Colangeli, Maria Morena, Allison Werner, Roger J. Thompson, Mario van der Stelt, Quentin J. Pittman, Matthew N. Hill, G. Campbell Teskey
Journal of Neuroscience 25 January 2023, 43 (4) 571-583; DOI: 10.1523/JNEUROSCI.0541-22.2022
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Keywords

  • electrophysiology
  • endocannabinoids
  • epilepsy
  • GABA
  • kindling
  • synaptic plasticity

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