PMID- 24475741 OWN - NLM STAT- MEDLINE DCOM- 20140615 LR - 20211021 IS - 1471-4159 (Electronic) IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 129 IP - 4 DP - 2014 May TI - Evidence that BDNF regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability. PG - 573-80 LID - 10.1111/jnc.12656 [doi] AB - Autonomic control of heart rate is mediated by cardioinhibitory parasympathetic cholinergic neurons located in the brainstem and stimulatory sympathetic noradrenergic neurons. During embryonic development the survival and cholinergic phenotype of brainstem autonomic neurons is promoted by brain-derived neurotrophic factor (BDNF). We now provide evidence that BDNF regulates heart rate by a mechanism involving increased brainstem cardioinhibitory parasympathetic activity. Mice with a BDNF haploinsufficiency exhibit elevated resting heart rate, and infusion of BDNF intracerebroventricularly reduces heart rate in both wild-type and BDNF+/- mice. The atropine-induced elevation of heart rate is diminished in BDNF+/- mice and is restored by BDNF infusion, whereas the atenolol-induced decrease in heart rate is unaffected by BDNF levels, suggesting that BDNF signaling enhances parasympathetic tone which is diminished with BDNF haploinsufficiency. Whole-cell recordings from pre-motor cholinergic cardioinhibitory vagal neurons in the nucleus ambiguus indicate that BDNF haploinsufficiency reduces cardioinhibitory vagal neuron activity by increased inhibitory GABAergic and diminished excitatory glutamatergic neurotransmission to these neurons. Our findings reveal a previously unknown role for BDNF in the control of heart rate by a mechanism involving increased activation of brainstem cholinergic parasympathetic neurons. CI - Published 2014. This article is a U.S. Government work and is in the public domain in the USA. FAU - Wan, Ruiqian AU - Wan R AD - Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, USA. FAU - Weigand, Letitia A AU - Weigand LA FAU - Bateman, Ryan AU - Bateman R FAU - Griffioen, Kathleen AU - Griffioen K FAU - Mendelowitz, David AU - Mendelowitz D FAU - Mattson, Mark P AU - Mattson MP LA - eng GR - HL72006/HL/NHLBI NIH HHS/United States GR - R01 HL072006/HL/NHLBI NIH HHS/United States GR - HL49965/HL/NHLBI NIH HHS/United States GR - R01 HL049965/HL/NHLBI NIH HHS/United States GR - R01 HL059895/HL/NHLBI NIH HHS/United States GR - HL59895/HL/NHLBI NIH HHS/United States GR - ZIA AG000317-12/Intramural NIH HHS/United States GR - ZIA AG000314-13/Intramural NIH HHS/United States GR - ZIA AG000317-13/Intramural NIH HHS/United States GR - ZIA AG000314-12/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140210 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Recombinant Proteins) RN - 3KX376GY7L (Glutamic Acid) RN - 50VV3VW0TI (Atenolol) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - 7171WSG8A2 (BDNF protein, human) RN - 7C0697DR9I (Atropine) SB - IM MH - Animals MH - Atenolol/pharmacology MH - Atropine/pharmacology MH - Brain Stem/*physiology MH - Brain-Derived Neurotrophic Factor/administration & dosage/deficiency/pharmacology/*physiology MH - Cholinergic Fibers/drug effects/physiology MH - Excitatory Postsynaptic Potentials MH - Glutamic Acid/physiology MH - Heart Rate/*physiology MH - Humans MH - Infusions, Intraventricular MH - Inhibitory Postsynaptic Potentials MH - Male MH - Mice MH - Mice, Congenic MH - Neurons/physiology MH - Parasympathetic Nervous System/drug effects/*physiology MH - Patch-Clamp Techniques MH - Recombinant Proteins/administration & dosage/pharmacology MH - Vagus Nerve/drug effects/physiology MH - gamma-Aminobutyric Acid/physiology PMC - PMC4137462 MID - NIHMS561276 OTO - NOTNLM OT - BDNF OT - GABA OT - glutamate OT - nucleus ambiguus OT - parasympathetic OT - vagus nerve COIS- conflict of interest disclosure The authors declare that they have no conflicts of interest. EDAT- 2014/01/31 06:00 MHDA- 2014/06/16 06:00 PMCR- 2015/05/01 CRDT- 2014/01/31 06:00 PHST- 2013/12/09 00:00 [received] PHST- 2014/01/09 00:00 [accepted] PHST- 2014/01/31 06:00 [entrez] PHST- 2014/01/31 06:00 [pubmed] PHST- 2014/06/16 06:00 [medline] PHST- 2015/05/01 00:00 [pmc-release] AID - 10.1111/jnc.12656 [doi] PST - ppublish SO - J Neurochem. 2014 May;129(4):573-80. doi: 10.1111/jnc.12656. Epub 2014 Feb 10.