Journal
EUROPEAN NEUROPSYCHOPHARMACOLOGY
Volume 28, Issue 1, Pages 195-210Publisher
ELSEVIER
DOI: 10.1016/j.euroneuro.2017.11.002
Keywords
Major depressive disorder; Social defeat model; Proteomics; Protein interaction networks; Intracranial-self-stimulation; Selected reaction monitoring; Fluoxetine; Donepezil
Funding
- SMRI Grant [07R-1888]
- Innovative Medicines Initiative Joint Undertaking [115008]
- European Union
- Engineering and Physical Sciences Research Council [1351685] Funding Source: researchfish
Ask authors/readers for more resources
While anhedonia is considered a core symptom of major depressive disorder (MDD), less attention has been paid to cognitive dysfunctions. We evaluated the behavioural and molecular effects of a selective serotonin re-uptake inhibitor (SSRI, fluoxetine) and an acetylcholinesterase inhibitor (AChEI, donepezil) on emotional-cognitive endophenotypes of depression and the hippocampal proteome. A chronic social defeat (SD) procedure was followed up by reminder sessions of direct and indirect SD. Anhedonia-related behaviour was assessed longitudinally by intracranial self-stimulation (ICSS). Cognitive dysfunction was analysed by an object recognition test (ORT) and extinction of fear memory. Tandem mass spectrometry (MSE) and protein protein -interaction (PPI) network modelling were used to characterise the underlying biological processes of SD and SSRI/AChEl treatment. Independent selected reaction monitoring (SRM) was conducted for molecular validation. Repeated SD resulted in a stable increase of anhedonia-like behaviour as measured by ICSS. Fluoxetine treatment reversed this phenotype, whereas donepezil showed no effect. Fluoxetine improved recognition memory and inhibitory learning in a stressor-related context, whereas donepezil only improved fear extinction. MSE and PPI network analysis highlighted functional SD stress-related hippocampal proteome changes including reduced glutamatergic neurotransmission and learning processes, which were reversed by fluoxetine, but not by donepezil. SRM validation of molecular key players involved in these pathways confirmed the hypothesis that fluoxetine acts via increased AMPA receptor signalling and Ca2+-mediated neuroplasticity in the amelioration of stress-impaired reward processing and memory consolidation. Our study highlights molecular mediators of SD stress reversed by SSRI treatment, identifying potential viable future targets to improve cognitive dysfunctions in MDD patients. (C) 2017 Elsevier B.V. and ECNP. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available