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Changes in signaling pathways regulating neuroplasticity induced by neurokinin 1 receptor knockout

Authors

  • Laura Musazzi,

    1. Center of Neuropharmacology-Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9-20133 Milano, Italy
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  • Jorge Perez,

    1. Biological Psychiatry Unit, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy
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  • Stephen P. Hunt,

    1. Department of Anatomy and Developmental Biology, Medawar Building, UCL, London, UK
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  • Giorgio Racagni,

    1. Center of Neuropharmacology-Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9-20133 Milano, Italy
    2. Biological Psychiatry Unit, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy
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  • Maurizio Popoli

    1. Center of Neuropharmacology-Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti 9-20133 Milano, Italy
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Dr Maurizio Popoli, as above.
E-mail: maurizio.popoli@unimi.it

Abstract

Neurokinin 1 (NK-1) receptor knockout mice showed behavioral responses similar to animals chronically treated with antidepressants. The aim of this study was to analyse, in NK-1 receptor knockout, the molecular modifications of signaling pathways involved in the pathophysiology of depression and antidepressant mechanism. We found, in total cell cytosol from the prefrontal/frontal cortex, hippocampus and striatum, a marked up-regulation of Ca2+-independent enzymatic activity and Thr286 autophosphorylation of Ca2+/calmodulin-dependent protein kinase (CaMK) II. Similar changes in CaMKII regulation were previously observed in rats chronically treated with antidepressants. In striatum, up-regulation of the activity and phosphorylation of CaMKII was also found in the homogenate and synaptosomes. No major changes were observed in the Ca2+-dependent kinase activity, with the exception of homogenate from the prefrontal/frontal cortex. We also analysed the expression and phosphorylation of presynaptic proteins, which modulate synaptic vesicle trafficking and exocytosis, and found a marked decrease in synapsin I total expression and basal phosphorylation of Ser603 (the phosphorylation site for CaMKII) in the prefrontal/frontal cortex. Accordingly, the Ca2+/calmodulin-dependent posthoc endogenous phosphorylation of synapsin I in the same area was increased. The knockout of NK-1 receptor had no consequences on the expression or phosphorylation levels of the transcription factor cAMP-responsive element-binding protein and its regulating kinase CaMKIV. However, phosphorylation of ERK1/2-mitogen-activated protein kinases was reduced in the hippocampus and striatum, again resembling an effect previously observed in antidepressant-treated rats. These results show similarities between NK-1 knockouts and animals chronically treated with antidepressants and support the putative antidepressant activity of NK-1 receptor antagonists.

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