title: Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Delta9-THC exposure-impaired hippocampal synaptic plasticity.
abstract: Chronic use of marijuana impairs synaptic plasticity and cognitive function. However, the molecular mechanisms by which marijuana alters long-term synaptic plasticity are largely unknown. Here, we show that repeated in vivo exposures to Delta9-THC for 7 consecutive days significantly impaired hippocampal long-term potentiation (LTP) of excitatory glutamatergic synaptic transmission. The Delta9-THC exposure-induced decrease in LTP was prevented by pharmacological inhibition or deletion of the cannabinoid 1 receptor (CB1R). To determine the molecular mechanisms underlying Delta9-THC-altered LTP, we targeted expression and function of the glutamate receptors (GluR) and phosphorylation status of cAMP-response element-binding protein (CREB). Chronic in vivo exposure to Delta9-THC produced CB1R-dependent decreases in expression of hippocampal GluR1, NR2A, and NR2B, the ratio of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/NMDA receptor-gated currents, and phosphorylation of CREB. Our results suggest that reduced expression and function of the GluR subunits and phosphorylation of CREB may underlie the impaired long-term synaptic plasticity induced by repeated in vivo exposure to Delta9-THC.
authors.affiliation: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: Ni
authors.initials: N
authors.lastname: Fan
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001703:Biophysics; D019921:Biotinylation; D050882:CREB-Binding Protein / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques / Q000379:methods; D010766:Phosphorylation / Q000187:drug effects; D011619:Psychotropic Drugs / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000187:drug effects*
chemical_list: D015763:2-Amino-5-phosphonovalerate; D001640:Bicuculline; D050882:CREB-Binding Protein; D013759:Dronabinol; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D011619:Psychotropic Drugs; D043884:Receptor, Cannabinoid, CB1; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor