QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.131607v1 325/3/850    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kim, H. J. Articles by Thayer, S. A. PubMed PubMed Citation Articles by Kim, H. J. Articles by Thayer, S. A.

NEUROPHARMACOLOGY

Cannabinoids Inhibit Network-Driven Synapse Loss between Hippocampal Neurons in Culture

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota

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] (EC₅₀ = 2.5 ± 0.5 nM) and the partial agonist ⁹-tetrahydrocannabinol (THC; EC₅₀ = 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.

Address correspondence to: Dr. Stanley A. Thayer, Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street, Minneapolis, MN 55455. E-mail: sathayer{at}umn.edu