Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus

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Abstract

Endocannabinoid signaling is a key regulator of synaptic neurotransmission throughout the brain. Compelling evidence shows that its perturbation leads to development of epileptic seizures, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. To elucidate whether long-term reorganization of endocannabinoid signaling occurs in epileptic patients, we performed comparative expression profiling along with quantitative electron microscopic analysis in control (postmortem samples from subjects with no signs of neurological disorders) and epileptic (surgically removed from patients with intractable temporal lobe epilepsy) hippocampal tissue. Quantitative PCR measurements revealed that CB1 cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus. Likewise, the cannabinoid receptor-interacting protein-1a mRNA was decreased, whereas 1b isoform levels were unaltered. Expression of diacylglycerol lipase-α, an enzyme responsible for 2-arachidonoylglycerol synthesis, was also reduced by ∼60%, whereas its related β isoform levels were unchanged. Expression level of N-acyl-phosphatidylethanolamine- hydrolyzing phospholipase D and fatty acid amide hydrolase, metabolic enzymes of anandamide, and 2-arachidonoylglycerol's degrading enzyme monoacylglycerol lipase did not change. The density of CB1 immunolabeling was also decreased in epileptic hippocampus, predominantly in the dentate gyrus, where quantitative electron microscopic analysis did not reveal changes in the ratio of CB1-positive GABAergic boutons, but uncovered robust reduction in the fraction of CB1-positive glutamatergic axon terminals. These findings show that a neuroprotective machinery involving endocannabinoids is impaired in epileptic human hippocampus and imply that downregulation of CB 1 receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.

Original languageEnglish
Pages (from-to)2976-2990
Number of pages15
JournalJournal of Neuroscience
Volume28
Issue number12
DOIs
Publication statusPublished - Mar 19 2008

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Cannabinoid Receptor CB1
Endocannabinoids
Hippocampus
Down-Regulation
Protein Isoforms
Enzymes
Monoacylglycerol Lipases
Receptor-Interacting Protein Serine-Threonine Kinases
Electrons
Cannabinoid Receptors
Phospholipase D
Messenger RNA
Temporal Lobe Epilepsy
Lipoprotein Lipase
Dentate Gyrus
Presynaptic Terminals
Nervous System Diseases
Synaptic Transmission
Epilepsy
Polymerase Chain Reaction

Keywords

  • 2-AG
  • Cannabinoid
  • CB
  • CRIP
  • DGL
  • Temporal lobe epilepsy

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

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title = "Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus",
abstract = "Endocannabinoid signaling is a key regulator of synaptic neurotransmission throughout the brain. Compelling evidence shows that its perturbation leads to development of epileptic seizures, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. To elucidate whether long-term reorganization of endocannabinoid signaling occurs in epileptic patients, we performed comparative expression profiling along with quantitative electron microscopic analysis in control (postmortem samples from subjects with no signs of neurological disorders) and epileptic (surgically removed from patients with intractable temporal lobe epilepsy) hippocampal tissue. Quantitative PCR measurements revealed that CB1 cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus. Likewise, the cannabinoid receptor-interacting protein-1a mRNA was decreased, whereas 1b isoform levels were unaltered. Expression of diacylglycerol lipase-α, an enzyme responsible for 2-arachidonoylglycerol synthesis, was also reduced by ∼60{\%}, whereas its related β isoform levels were unchanged. Expression level of N-acyl-phosphatidylethanolamine- hydrolyzing phospholipase D and fatty acid amide hydrolase, metabolic enzymes of anandamide, and 2-arachidonoylglycerol's degrading enzyme monoacylglycerol lipase did not change. The density of CB1 immunolabeling was also decreased in epileptic hippocampus, predominantly in the dentate gyrus, where quantitative electron microscopic analysis did not reveal changes in the ratio of CB1-positive GABAergic boutons, but uncovered robust reduction in the fraction of CB1-positive glutamatergic axon terminals. These findings show that a neuroprotective machinery involving endocannabinoids is impaired in epileptic human hippocampus and imply that downregulation of CB 1 receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.",
keywords = "2-AG, Cannabinoid, CB, CRIP, DGL, Temporal lobe epilepsy",
author = "Anik{\'o} Lud{\'a}nyi and Lor{\'a}nd Eross and S{\'a}ndor Czirj{\'a}k and J{\'a}nos Vajda and P{\'e}ter Hal{\'a}sz and Masahiko Watanabe and Mikl{\'o}s Palkovits and Zs{\'o}fia Magl{\'o}czky and Freund, {Tam{\'a}s F.} and Istv{\'a}n Katona",
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T1 - Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus

AU - Ludányi, Anikó

AU - Eross, Loránd

AU - Czirják, Sándor

AU - Vajda, János

AU - Halász, Péter

AU - Watanabe, Masahiko

AU - Palkovits, Miklós

AU - Maglóczky, Zsófia

AU - Freund, Tamás F.

AU - Katona, István

PY - 2008/3/19

Y1 - 2008/3/19

N2 - Endocannabinoid signaling is a key regulator of synaptic neurotransmission throughout the brain. Compelling evidence shows that its perturbation leads to development of epileptic seizures, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. To elucidate whether long-term reorganization of endocannabinoid signaling occurs in epileptic patients, we performed comparative expression profiling along with quantitative electron microscopic analysis in control (postmortem samples from subjects with no signs of neurological disorders) and epileptic (surgically removed from patients with intractable temporal lobe epilepsy) hippocampal tissue. Quantitative PCR measurements revealed that CB1 cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus. Likewise, the cannabinoid receptor-interacting protein-1a mRNA was decreased, whereas 1b isoform levels were unaltered. Expression of diacylglycerol lipase-α, an enzyme responsible for 2-arachidonoylglycerol synthesis, was also reduced by ∼60%, whereas its related β isoform levels were unchanged. Expression level of N-acyl-phosphatidylethanolamine- hydrolyzing phospholipase D and fatty acid amide hydrolase, metabolic enzymes of anandamide, and 2-arachidonoylglycerol's degrading enzyme monoacylglycerol lipase did not change. The density of CB1 immunolabeling was also decreased in epileptic hippocampus, predominantly in the dentate gyrus, where quantitative electron microscopic analysis did not reveal changes in the ratio of CB1-positive GABAergic boutons, but uncovered robust reduction in the fraction of CB1-positive glutamatergic axon terminals. These findings show that a neuroprotective machinery involving endocannabinoids is impaired in epileptic human hippocampus and imply that downregulation of CB 1 receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.

AB - Endocannabinoid signaling is a key regulator of synaptic neurotransmission throughout the brain. Compelling evidence shows that its perturbation leads to development of epileptic seizures, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. To elucidate whether long-term reorganization of endocannabinoid signaling occurs in epileptic patients, we performed comparative expression profiling along with quantitative electron microscopic analysis in control (postmortem samples from subjects with no signs of neurological disorders) and epileptic (surgically removed from patients with intractable temporal lobe epilepsy) hippocampal tissue. Quantitative PCR measurements revealed that CB1 cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus. Likewise, the cannabinoid receptor-interacting protein-1a mRNA was decreased, whereas 1b isoform levels were unaltered. Expression of diacylglycerol lipase-α, an enzyme responsible for 2-arachidonoylglycerol synthesis, was also reduced by ∼60%, whereas its related β isoform levels were unchanged. Expression level of N-acyl-phosphatidylethanolamine- hydrolyzing phospholipase D and fatty acid amide hydrolase, metabolic enzymes of anandamide, and 2-arachidonoylglycerol's degrading enzyme monoacylglycerol lipase did not change. The density of CB1 immunolabeling was also decreased in epileptic hippocampus, predominantly in the dentate gyrus, where quantitative electron microscopic analysis did not reveal changes in the ratio of CB1-positive GABAergic boutons, but uncovered robust reduction in the fraction of CB1-positive glutamatergic axon terminals. These findings show that a neuroprotective machinery involving endocannabinoids is impaired in epileptic human hippocampus and imply that downregulation of CB 1 receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.

KW - 2-AG

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KW - CRIP

KW - DGL

KW - Temporal lobe epilepsy

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