Depolarization promotes survival of ciliary ganglion neurons by BDNF-dependent and -independent mechanisms.
Membrane activity upregulates brain derived neurotrophic factor (BDNF) expression to coordinately support neuronal survival in many systems. In parasympathetic ciliary ganglion (CG) neurons, activity mimicked by KCl depolarization provides nearly full trophic support. While BDNF has been considered unable to influence CG neuronal survival, we now document its expression during CG development and show that low concentrations do support survival via high-affinity TrkB receptors. Furthermore, a contribution of BDNF to activity-induced trophic support was demonstrated by showing that KCl depolarization increased BDNF mRNA and protein in, and release of BDNF from, CG neuron cultures. Application of anti-BDNF blocking antibody or mitogen activated protein kinase (MAPK) kinase inhibitor, attenuated depolarization-supported survival, implicating canonical BDNF/TrkB signaling. Ca2+-Calmodulin kinase II (CaMKII) was also required since its inhibition combined with anti-BDNF or MAPK kinase inhibitor abolished or greatly reduced the trophic effects of depolarization. Membrane activity may thus support CG neuronal survival both by stimulating release of BDNF that binds high-affinity TrkB receptors to activate MAPK and by recruiting CaMKII. This mechanism could have relevance late in development in vivo as ganglionic transmission and the effectiveness of BDNF over other growth factors both increase.
Pugh
Phyllis C
PC
Department of Neurosciences, Medical University of Ohio, Block HS 108, 3035 Arlington Ave., Toledo, OH 43614, USA.
Zhou
Xiangdong
X
Jayakar
Selwyn S
SS
Margiotta
Joseph F
JF
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002642:Chick Embryo; D004622:Embryo, Mammalian / Q000166:cytology; D004625:Embryo, Nonmammalian; D005726:Ganglia, Parasympathetic / Q000166:cytology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction
D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D011189:Potassium Chloride; D020813:Receptor, trkB; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases