Abstract
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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Behavior, Animal / drug effects
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Benzoxazines
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Calcium Channel Blockers / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Cannabinoid Receptor Modulators / physiology*
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Endocannabinoids*
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Epilepsy / chemically induced
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Epilepsy / genetics
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Epilepsy / pathology*
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Epilepsy / physiopathology*
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Gene Expression / physiology
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Glutamic Acid / genetics
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Glutamic Acid / metabolism
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Hippocampus / drug effects
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Hippocampus / pathology*
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Hippocampus / physiopathology
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Kainic Acid / toxicity
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Membrane Potentials / radiation effects
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Morpholines / pharmacology
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Naphthalenes / pharmacology
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Nerve Net / drug effects
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Nerve Net / pathology*
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Nerve Net / physiopathology
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Pyramidal Cells / physiology
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Pyramidal Cells / radiation effects
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Receptor, Cannabinoid, CB1 / deficiency
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Vesicular Glutamate Transport Protein 1 / metabolism
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gamma-Aminobutyric Acid / genetics
Substances
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Benzoxazines
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Calcium Channel Blockers
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Cannabinoid Receptor Modulators
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Endocannabinoids
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Morpholines
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Naphthalenes
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Receptor, Cannabinoid, CB1
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Slc17a7 protein, mouse
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Vesicular Glutamate Transport Protein 1
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Glutamic Acid
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gamma-Aminobutyric Acid
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Kainic Acid