title: Ketamine regulates the presynaptic release machinery in the hippocampus.
abstract: In the search for new drug targets, that may help point the way to develop fast-acting treatments for mood disorders, we have explored molecular pathways regulated by ketamine, an NMDA receptor antagonist, which has consistently shown antidepressant response within a few hours of administration. Using Sprague-Dawley rats we investigated the effects of ketamine on the presynaptic release machinery responsible for neurotransmitter release at 1, 2 and 4 h as well as 7 days after administration of a single subanesthetic dose of ketamine (15 mg/kg). A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after 1, 2 and 4 h of ketamine administration. In parallel, we found a selective reduction in the expression of the synaptic vesicle protein synaptotagmin I and an increase in the levels of synapsin I in hippocampal synaptosomes suggesting a mechanism by which ketamine reduces SNARE complex formation, in part, by regulating the number of synaptic vesicles in the nerve terminals. Moreover, ketamine reduced Thr(286)-phosphorylated αCaMKII and its interaction with syntaxin 1A, which identifies CaMKII as a potential target for second messenger-mediated actions of ketamine. In addition, despite previous reports of ketamine-induced inhibition of GSK-3, we were unable to detect regulation of its activity after ketamine administration. Our findings demonstrate that ketamine rapidly induces changes in the hippocampal presynaptic machinery similar to those that are obtained only with chronic treatments with traditional antidepressants. This suggests that reduction of neurotransmitter release in the hippocampus has possible relevance for the rapid antidepressant effect of ketamine.
authors.affiliation: Centre for Psychiatric Research, Aarhus University Hospital, Skovagervej 2, DK-8240 Risskov, Denmark. heidmull@rm.dk
authors.forename: Heidi Kaastrup
authors.initials: HK
authors.lastname: Müller
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
authors.forename: Nico
authors.initials: N
authors.lastname: Liebenberg
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
authors.forename: Maurizio
authors.initials: M
authors.lastname: Popoli
authors.forename: Betina
authors.initials: B
authors.lastname: Elfving
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D047468:Immunoprecipitation; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051938:Munc18 Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050600:SNARE Proteins / Q000378:metabolism*; D013550:Swimming / Q000523:psychology; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000648:ultrastructure; D050863:Synaptotagmin I / Q000378:metabolism; D013997:Time Factors
chemical_list: D000929:Antidepressive Agents, Tricyclic; D018691:Excitatory Amino Acid Antagonists; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D050600:SNARE Proteins; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D050863:Synaptotagmin I; D007649:Ketamine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003891:Desipramine
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