Tanasic, Sascha and Mattusch, Corinna and Wagner, Eva Maria and Eder, Matthias and Rupprecht, Rainer and Rammes, Gerhard and Di Benedetto, Barbara (2016) Desipramine targets astrocytes to attenuate synaptic plasticity via modulation of the ephrinA3/EphA4 signalling. NEUROPHARMACOLOGY, 105. pp. 154-163. ISSN 0028-3908, 1873-7064
Full text not available from this repository. (Request a copy)Abstract
Long-term potentiation (LTP), a major cellular correlate of memory storage, depends on activation of the ERK/MAPK signalling pathway, but the cell type-specific localization of activated MAPKs remains unknown. We found that in the CM field of the hippocampus, shortly after LTP induction, an increase in the number of MAPK-positive cells occurred specifically among astrocytes of the stratum radiatum, suggesting a putative role of astrocytes for LTP. Desipramine (DMI) is an antidepressant which is used to treat major depressive disorder, but also other pathologies such as neuropathic pain or attention-deficit/hyperactivity disorder. Tricyclic antidepressants such as DMI may cause memory impairment as a side effect. However, biological underpinnings of this effect still remain unclear. Here, we show that DMI inhibited the astrocytic MAPK activation and thereby hindered synaptic potentiation. These effects correlated with a reduced neuronal activation in the stratum pyramidale, thereby prompting us to analyse a regulator of LTP located at the astrocyte-neuron interface in the stratum radiatum, namely the ephrinA3/EphA4 signalling pathway. DMI enhanced EphA4 clustering, which favoured an increased ephrinA3-mediated EphA4 phosphorylation and elevated EphA4 forward signalling. The co-administration of DMI with the Src inhibitor SU6656, which blocks EphA4 forward signalling, could partially reverse the LTP attenuation, further supporting the targeting of the ephrinA3/EphA4 pathway by DMI. Thus, our findings suggest a putative novel mechanism for DMI to modulate LTP through the regulation of the ephrinA3/EphA4 signalling pathway. A further exploration of the molecular and behavioral consequences of targeting ephrinA3/EphA4 might help to improve the clinical use of DMI. (C) 2016 Elsevier Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LONG-TERM POTENTIATION; DENDRITIC SPINE MORPHOLOGY; ACTIVATED PROTEIN-KINASE; TRICYCLIC ANTIDEPRESSANTS; STRUCTURAL PLASTICITY; GLUTAMATE TRANSPORT; RECEPTOR; RELEASE; CELLS; GLIA; Desipramine; astrocytes; Synaptic plasticity; ephrinA3/EphA4 signalling |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Mar 2019 13:01 |
| Last Modified: | 22 Mar 2019 13:01 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2865 |
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