Abstract
Changes in synaptic plasticity are involved in pathophysiology of depression and in the mechanism of antidepressants. Ca2+/calmodulin (CaM) kinase II, a protein kinase involved in synaptic plasticity, has been previously shown to be a target of antidepressants. We previously found that antidepressants activate the kinase in hippocampal neuronal cell bodies by increasing phosphorylation at Thr286, reduce the kinase phosphorylation in synaptic membranes, and in turn its phosphorylation-dependent interaction with syntaxin-1 and the release of glutamate from hippocampal synaptosomes. Here, we investigated the chronic effect of different antidepressants (fluoxetine, desipramine, and reboxetine) on the expression and function of the kinase in distinct subcellular compartments in order to dissect the different kinase pools affected. Acute treatments did not induce any change in the kinase. In total tissue extracts chronic drug treatments induced activation of the kinase; in hippocampus (HC), but not in prefrontal/frontal cortex, this was partially accounted for by increased Thr286 phosphorylation, suggesting the involvement of different mechanisms of activation. In synaptosomes, all drugs reduced the kinase phosphorylation, particularly in HC where, upon fractionation of the synaptosomal particulate into synaptic vesicles and membranes, we found that the drugs induced a redistribution and differential activation of the kinase between membranes and vesicles. Furthermore, a large decrease in the level and phosphorylation of synapsin I located at synaptic membranes was consistent with the observed decrease of CaM kinase II. Overall, antidepressants induce a complex pattern of modifications in distinct subcellular compartments; at presynaptic level, these changes are in line with a dampening of glutamate release.
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Acknowledgements
This study was supported by Grants from NARSAD (USA) to MP and from Ministry of University, PRIN # 2001054224 and 2003053993 to GR and MP (Italy). RG was founded by the PhD Program in Neuropharmacology, University of Catania Medical School.
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Barbiero, V., Giambelli, R., Musazzi, L. et al. Chronic Antidepressants Induce Redistribution and Differential Activation of αCaM Kinase II between Presynaptic Compartments. Neuropsychopharmacol 32, 2511–2519 (2007). https://doi.org/10.1038/sj.npp.1301378
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DOI: https://doi.org/10.1038/sj.npp.1301378
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