Tianeptine potentiates AMPA receptors by activating CaMKII and PKA via the p38, p42/44 MAPK and JNK pathways

Viktor Szegedi, Gábor Juhász, Xiaoqun Zhang, Balázs Barkóczi, Hongshi Qi, Alexandra Madeira, Gábor Kapus, Per Svenningsson, Michael Spedding, Botond Penke

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Impairments of cellular plasticity appear to underlie the pathophysiology of major depression. Recently, elevated levels of phosphorylated AMPA receptor were implicated in the antidepressant effect of various drugs. Here, we investigated the effects of an antidepressant, Tianeptine, on synaptic function and GluA1 phosphorylation using murine hippocampal slices and in vivo single-unit recordings. Tianeptine, but not imipramine, increased AMPA receptor-mediated neuronal responses both in vitro and in vivo, in a staurosporine-sensitive manner. Paired-pulse ratio was unaltered by Tianeptine, suggesting a postsynaptic site of action. Tianeptine, 10 μM, enhanced the GluA1-dependent initial phase of LTP, whereas 100 μM impaired the latter phases, indicating a critical role of GluA1 subunit phosphorylation in the excitation. Tianeptine rapidly increased the phosphorylation level of Ser 831-GluA1 and Ser 845-GluA1. Using H-89 and KN-93, we show that the activation of both PKA and CaMKII is critical in the effect of Tianeptine on AMPA responses. Moreover, the phosphorylation states of Ser 217/221-MEK and Thr 183/Tyr 185-p42MAPK were increased by Tianeptine and specific kinase blockers of the MAPK pathways (PD 98095, SB 203580 and SP600125) prevented the effects of Tianeptine. Overall these data suggest that Tianeptine potentiates several signaling cascades associated with synaptic plasticity and provide further evidence that a major mechanism of action for Tianeptine is to act as an enhancer of glutamate neurotransmission via AMPA receptors.

Original languageEnglish
Pages (from-to)1109-1122
Number of pages14
JournalNeurochemistry international
Volume59
Issue number8
DOIs
Publication statusPublished - Dec 1 2011

Keywords

  • Antidepressant
  • Glutamate receptors
  • NMDA
  • Phosphorylation
  • Signaling pathway
  • Synaptic plasticity

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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