PMID- 24704572 OWN - NLM STAT- MEDLINE DCOM- 20150227 LR - 20140619 IS - 1873-7528 (Electronic) IS - 0149-7634 (Linking) VI - 43 DP - 2014 Jun TI - The serotonin-BDNF duo: developmental implications for the vulnerability to psychopathology. PG - 35-47 LID - S0149-7634(14)00066-9 [pii] LID - 10.1016/j.neubiorev.2014.03.012 [doi] AB - Serotonin (5-HT) and brain-derived neurotrophin factor (BDNF) are known to modulate behavioral responses to stress and to mediate the therapeutic efficacy of antidepressant agents through neuroplastic and epigenetic mechanisms. While the two systems interact at several levels, this scenario is complicated by a number of variants including brain region specificity, 5-HT receptor selectivity and timing. Based on recent insights obtained using 5-HT transporter (5-HTT) knockout rats we here set-out and discuss the crucial role of neurodevelopmental mechanisms and the contribution of transcription factors and epigenetic modifications to this interaction and its variants. 5-HTT knockout in rats, as well as the low activity short allelic variant of the serotonin transporter human polymorphism, consistently show reduced BDNF mRNA and protein levels in the hippocampus and in the prefrontal cortex. This starts during the second postnatal week, is preceded by DNA hypermethylation during the first postnatal week, and it is developmentally paralleled by reduced expression of key transcription factors. The reduced BDNF levels, in turn, affect 5-HT1A receptor-mediated intracellular signaling and thereby the serotonergic phenotype of the neurons. We propose that such a negative spiral of modifications may affect brain development and reduce its resiliency to environmental challenges during critical time windows, which may lead to phenotypic alterations that persist for the entire life. The characterization of 5-HT-BDNF interactions will eventually increase the understanding of mental illness etiology and, possibly, lead to the identification of novel molecular targets for drug development. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Homberg, Judith Regina AU - Homberg JR AD - Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21, 6525 EZ Nijmegen, The Netherlands. FAU - Molteni, Raffaella AU - Molteni R AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. FAU - Calabrese, Francesca AU - Calabrese F AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. FAU - Riva, Marco A AU - Riva MA AD - Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. Electronic address: M.Riva@unimi.it. LA - eng PT - Journal Article PT - Review DEP - 20140403 PL - United States TA - Neurosci Biobehav Rev JT - Neuroscience and biobehavioral reviews JID - 7806090 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Serotonin Plasma Membrane Transport Proteins) RN - 333DO1RDJY (Serotonin) SB - IM MH - Animals MH - Brain/*metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Humans MH - Neuronal Plasticity/*physiology MH - Psychopathology MH - Serotonin/*metabolism MH - Serotonin Plasma Membrane Transport Proteins/metabolism OTO - NOTNLM OT - 5-HTT OT - BDNF OT - DNA methylation OT - Depression OT - Neurodevelopment OT - Serotonin OT - Transcription factors EDAT- 2014/04/08 06:00 MHDA- 2015/02/28 06:00 CRDT- 2014/04/08 06:00 PHST- 2013/09/30 00:00 [received] PHST- 2014/03/03 00:00 [revised] PHST- 2014/03/06 00:00 [accepted] PHST- 2014/04/08 06:00 [entrez] PHST- 2014/04/08 06:00 [pubmed] PHST- 2015/02/28 06:00 [medline] AID - S0149-7634(14)00066-9 [pii] AID - 10.1016/j.neubiorev.2014.03.012 [doi] PST - ppublish SO - Neurosci Biobehav Rev. 2014 Jun;43:35-47. doi: 10.1016/j.neubiorev.2014.03.012. Epub 2014 Apr 3.