The endocannabinoid system controls key epileptogenic circuits in the hippocampus.
Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.
Monory
Krisztina
K
Department of Physiological Chemistry, Johannes Gutenberg University, Duesbergweg 6, 55099 Mainz, Germany.
Massa
Federico
F
Egertová
Michaela
M
Eder
Matthias
M
Blaudzun
Heike
H
Westenbroek
Ruth
R
Kelsch
Wolfgang
W
Jacob
Wolfgang
W
Marsch
Rudolf
R
Ekker
Marc
M
Long
Jason
J
Rubenstein
John L
JL
Goebbels
Sandra
S
Nave
Klaus-Armin
KA
During
Matthew
M
Klugmann
Matthias
M
Wölfel
Barbara
B
Dodt
Hans-Ulrich
HU
Zieglgänsberger
Walter
W
Wotjak
Carsten T
CT
Mackie
Ken
K
Elphick
Maurice R
MR
Marsicano
Giovanni
G
Lutz
Beat
B
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines; D002121:Calcium Channel Blockers / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D063388:Endocannabinoids; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009415:Nerve Net / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D017966:Pyramidal Cells / Q000502:physiology / Q000528:radiation effects; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000235:genetics
D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D007608:Kainic Acid