PMID- 26585288 OWN - NLM STAT- MEDLINE DCOM- 20180115 LR - 20181113 IS - 1740-634X (Electronic) IS - 0893-133X (Print) IS - 0893-133X (Linking) VI - 41 IP - 8 DP - 2016 Jul TI - Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling. PG - 1943-55 LID - 10.1038/npp.2015.349 [doi] AB - Brain-derived neurotrophic factor (BDNF) regulates diverse biological functions ranging from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult. BDNF disruption in both rodents and humans is associated with neurobehavioral alterations and psychiatric disorders. A unique feature of Bdnf transcription is regulation by nine individual promoters, which drive expression of variants that encode an identical protein. It is hypothesized that this unique genomic structure may provide flexibility that allows different factors to regulate BDNF signaling in distinct cell types and circuits. This has led to the suggestion that isoforms may regulate specific BDNF-dependent functions; however, little scientific support for this idea exists. We generated four novel mutant mouse lines in which BDNF production from one of the four major promoters (I, II, IV, or VI) is selectively disrupted (Bdnf-e1, -e2, -e4, and -e6 mice) and used a comprehensive comparator approach to determine whether different Bdnf transcripts are associated with specific BDNF-dependent molecular, cellular, and behavioral phenotypes. Bdnf-e1 and -e2 mutant males displayed heightened aggression accompanied by convergent expression changes in specific genes associated with serotonin signaling. In contrast, BDNF-e4 and -e6 mutants were not aggressive but displayed impairments associated with GABAergic gene expression. Moreover, quantifications of BDNF protein in the hypothalamus, prefrontal cortex, and hippocampus revealed that individual Bdnf transcripts make differential, region-specific contributions to total BDNF levels. The results highlight the biological significance of alternative Bdnf transcripts and provide evidence that individual isoforms serve distinct molecular and behavioral functions. FAU - Maynard, Kristen R AU - Maynard KR AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. FAU - Hill, Julia L AU - Hill JL AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. FAU - Calcaterra, Nicholas E AU - Calcaterra NE AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. FAU - Palko, Mary E AU - Palko ME AD - National Cancer Institute, Frederick, MD, USA. FAU - Kardian, Alisha AU - Kardian A AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. FAU - Paredes, Daniel AU - Paredes D AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. FAU - Sukumar, Mahima AU - Sukumar M AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. FAU - Adler, Benjamin D AU - Adler BD AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. FAU - Jimenez, Dennisse V AU - Jimenez DV AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. FAU - Schloesser, Robert J AU - Schloesser RJ AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. AD - Sheppard Pratt-Lieber Research Institute, Baltimore, MD, USA. FAU - Tessarollo, Lino AU - Tessarollo L AD - National Cancer Institute, Frederick, MD, USA. FAU - Lu, Bai AU - Lu B AD - Tsinghua University School of Medicine, Beijing, China. FAU - Martinowich, Keri AU - Martinowich K AD - Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. AD - Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. AD - Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. LA - eng GR - R01 MH105592/MH/NIMH NIH HHS/United States GR - T32 MH015330/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20151116 PL - England TA - Neuropsychopharmacology JT - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JID - 8904907 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (RNA, Messenger) RN - 333DO1RDJY (Serotonin) RN - 56-12-2 (gamma-Aminobutyric Acid) SB - IM CIN - Neuropsychopharmacology. 2016 Jul;41(8):1941-2. PMID: 27282104 MH - *Aggression MH - Animals MH - Brain/metabolism MH - Brain-Derived Neurotrophic Factor/*genetics MH - Gene Expression Regulation MH - Hippocampus/metabolism MH - Hypothalamus/metabolism MH - Mice MH - Mice, Transgenic MH - Neurons/metabolism MH - Prefrontal Cortex/metabolism MH - *Promoter Regions, Genetic MH - RNA, Messenger/metabolism MH - Serotonin/*metabolism MH - *Signal Transduction MH - gamma-Aminobutyric Acid/metabolism PMC - PMC4908631 EDAT- 2015/11/21 06:00 MHDA- 2018/01/16 06:00 PMCR- 2017/07/01 CRDT- 2015/11/21 06:00 PHST- 2015/09/03 00:00 [received] PHST- 2015/11/13 00:00 [revised] PHST- 2015/11/17 00:00 [accepted] PHST- 2015/11/21 06:00 [entrez] PHST- 2015/11/21 06:00 [pubmed] PHST- 2018/01/16 06:00 [medline] PHST- 2017/07/01 00:00 [pmc-release] AID - npp2015349 [pii] AID - 10.1038/npp.2015.349 [doi] PST - ppublish SO - Neuropsychopharmacology. 2016 Jul;41(8):1943-55. doi: 10.1038/npp.2015.349. Epub 2015 Nov 16.