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The Journal of Neuroscience, March 19, 2008, 28(12):2976-2990; doi:10.1523/JNEUROSCI.4465-07.2008

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Neurobiology of Disease
Downregulation of the CB₁ Cannabinoid Receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus

Anikó Ludányi,¹ Loránd Erss,² Sándor Czirják,² János Vajda,² Péter Halász,³ Masahiko Watanabe,⁴ Miklós Palkovits,⁵ Zsófia Maglóczky,¹ Tamás F. Freund,¹ and István Katona¹

¹Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, ²National Institute of Neurosurgery, H-1145 Budapest, Hungary, ³National Institute of Psychiatry and Neurology, Epilepsy Center, H-1021 Budapest, Hungary, ⁴Department of Anatomy, Hokkaido University School of Medicine, 060-8638 Sapporo, Japan, and ⁵Neuromorphological and Neuroendocrine Research Laboratory, Department of Anatomy, Semmelweis University and Hungarian Academy of Sciences, H-1094 Budapest, Hungary

Correspondence should be addressed to Dr. István Katona, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, H-1083 Budapest, Hungary. Email: katona{at}koki.hu

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-, 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 CB₁ receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.

Key words: DGL; CRIP; cannabinoid; CB₁; 2-AG; temporal lobe epilepsy

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Received Sept. 29, 2007; revised Jan. 21, 2008; accepted Feb. 7, 2008.

Correspondence should be addressed to Dr. István Katona, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, H-1083 Budapest, Hungary. Email: katona{at}koki.hu

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