NDLI: Cannabinoids inhibit network-driven synapse loss between hippocampal neurons in culture

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Kim, Hee Jung Waataja, Jonathan J. Thayer, Stanley A.
Description	Country affiliation: United States Author Affiliation: Kim HJ ( Department of Pharmacology, University of Minnesota Medical School, 321 Church Street, Minneapolis, MN 55455, USA.)
Abstract	Dendritic pruning and loss of synaptic contacts are early events in many neurodegenerative diseases. These effects are dynamic and seem to differ mechanistically from the cell death process. Cannabinoids modulate synaptic activity and afford protection in some neurotoxicity models. We investigated the effects of cannabinoids on activity-induced changes in the number of synapses between rat hippocampal neurons in culture. Morphology and synapses were visualized by confocal imaging of neurons expressing DsRed2 and postsynaptic density protein 95 (PSD95) fused to enhanced green fluorescent protein (GFP). Reducing the extracellular Mg2+ concentration to 0.1 mM for 4 h induced intense synaptic activity, which decreased the number of PSD95-GFP puncta by 45 +/- 13%. Synapse loss was an early event, required activation of N-methyl-D-aspartate receptors, and was mediated by the ubiquitin-proteasome pathway. The cannabinoid receptor full agonist WIN55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)-methyl] pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-napthalenyl)-methanone monomethanesulfonate] (EC(50) = 2.5 +/- 0.5 nM) and the partial agonist Delta(9)-tetrahydrocannabinol (THC; EC(50) = 9 +/- 3 nM) inhibited PSD loss in a manner reversed by the CB1 receptor antagonist rimonabant [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide]. The protection was mimicked by inhibition of presynaptic Ca2+ channels, and WIN55,212-2 did not prevent PSD loss elicited by direct application of glutamate, suggesting a presynaptic mechanism. Prolonged exposure to WIN55,212-2, but not THC, desensitized the protective effect. Treating cells that had undergone PSD loss with WIN55,212-2 reversed the loss and enabled recovery of a full compliment of synapses. The modulation of synaptic number by acute and prolonged exposure to cannabinoids may account for some of the effects of these drugs on the plasticity, survival, and function of neural networks.
File Format	HTM / HTML
ISSN	00223565
e-ISSN	15210103
DOI	10.1124/jpet.107.131607
Journal	Journal of Pharmacology and Experimental Therapeutics
Issue Number	3
Volume Number	325
Language	English
Publisher	American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2008-06-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Research Support, N.i.h., Extramural Neurons Cells, Cultured Cytology Pharmacology Benzoxazines Morpholines Discipline Pharmacology Drug Effects Naphthalenes Cannabinoids Animals Discipline Therapeutics Physiology Hippocampus Synapses
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Pharmacology

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