The antidepressant Tianeptine potentiates AMPA receptors by activating CaMKII and PKA via the p38 MAPK/MEK/JNK pathways
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1
University of Szeged, Department of Medical Chemistry, Hungary
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2
Bay Zoltán Foundation for Applied Research, BAYGEN, Hungary
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3
EGIS Pharmaceuticals Plc., Division of Preclinical Research, Hungary
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4
Institut de Rescherches Internationales Servier (IRIS), France
Increasing data suggest that impairments of cellular plasticity underlie the pathophysiology of major depression. Recently, a critical regulator of synaptic plasticity, AMPA receptor phosphorylation by CaMKII and PKA was implicated in the antidepressant effects of various drugs. Here, we investigated the effect of Tianeptine, an atypical antidepressant 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 way. Paired-pulse recordings were unaltered by Tianeptine, suggesting a postsynaptic site of action. Indeed, 10 µM Tianeptine enhanced the GluA1-dependent initial phase, whereas 100 µM impaired the latter phases of LTP, indicating a critical role of GluA1 subunit phosphorylation in the excitation. Using H-89 and KN-93, we show that the activation of both PKA and CaMKII was critical in this excitatory effect. Moreover, specific kinase blockers PD 98095, SB 203580 and SP600125 also prevented the fEPSP potentiating effect of Tianeptine, indicating that the stress related p38 MAPK, MEK and JNK pathways are involved in the excitation. Taken together, we propose that these molecular pathways may mediate the antidepressant effect of Tianeptine.
Conference:
IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010.
Presentation Type:
Poster Presentation
Topic:
Disorders of the nervous system
Citation:
Juhász
G,
Szegedi
V,
Barkóczi
B,
Kapus
G,
Spedding
M and
Penke
B
(2010). The antidepressant Tianeptine potentiates AMPA receptors by activating CaMKII and PKA via the p38 MAPK/MEK/JNK pathways.
Front. Neurosci.
Conference Abstract:
IBRO International Workshop 2010.
doi: 10.3389/conf.fnins.2010.10.00037
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Received:
20 Apr 2010;
Published Online:
20 Apr 2010.
*
Correspondence:
Gábor Juhász, University of Szeged, Department of Medical Chemistry, Szeged, Hungary, juhasz@dnt.u-szeged.hu