title: Desipramine targets astrocytes to attenuate synaptic plasticity via modulation of the ephrinA3/EphA4 signalling.
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 CA1 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.
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Tanasic
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany; Department of Anesthesiology, Technische University, 81675 Munich, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Mattusch
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Wagner
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany; Department of Psychiatry and Psychotherapy, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Rupprecht
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany; Department of Anesthesiology, Technische University, 81675 Munich, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rammes
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany; Department of Psychiatry and Psychotherapy, University of Regensburg, 93053 Regensburg, Germany. Electronic address: Barbara.Di-Benedetto@ukr.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Benedetto
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D003891:Desipramine / Q000008:administration & dosage*; D036384:Ephrin-A3 / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D036122:Receptor, EphA4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000929:Antidepressive Agents, Tricyclic; D036384:Ephrin-A3; D036122:Receptor, EphA4; D003891:Desipramine
keywords: Desipramine; Synaptic plasticity; astrocytes; ephrinA3/EphA4 signalling