Activity- and Ca2+-Dependent Modulation of Surface Expression of Brain-Derived Neurotrophic Factor Receptors in Hippocampal Neurons

Brain-derived neurotrophic factor (BDNF) has been shown to regulate neuronal survival and synaptic plasticity in the central nervous system (CNS) in an activity-dependent manner, but the underlying mechanisms remain unclear. Here we report that the number of BDNF receptor TrkB on the surface of hippocampal neurons can be enhanced by high frequency neuronal activity and synaptic transmission, and this effect is mediated by Ca2+ influx. Using membrane protein biotinylation as well as receptor binding assays, we show that field electric stimulation increased the number of TrkB on the surface of cultured hippocampal neurons. Immunofluorescence staining suggests that the electric stimulation facilitated the movement of TrkB from intracellular pool to the cell surface, particularly on neuronal processes. The number of surface TrkB was regulated only by high frequency tetanic stimulation, but not by low frequency stimulation. The activity dependent modulation appears to require Ca2+ influx, since treatment of the neurons with blockers of voltage-gated Ca2+ channels or NMDA receptors, or removal of extracellular Ca2+, severely attenuated the effect of electric stimulation. Moreover, inhibition of Ca2+/calmodulin-dependent kinase II (CaMKII) significantly reduced the effectiveness of the tetanic stimulation. These findings may help us to understand the role of neuronal activity in neurotrophin function and the mechanism for receptor tyrosine kinase signaling.

[1]  Y. Barde,et al.  Physiology of the neurotrophins. , 1996, Annual review of neuroscience.

[2]  R. Stephens,et al.  Neurotrophin signal transduction by the Trk receptor. , 1994, Journal of neurobiology.

[3]  C. Shatz,et al.  Synaptic Activity and the Construction of Cortical Circuits , 1996, Science.

[4]  C. Shatz,et al.  Developmental mechanisms that generate precise patterns of neuronal connectivity , 1993, Cell.

[5]  Yasuhisa Endo,et al.  Brain‐Derived Neurotrophic Factor Increases the Stimulation‐Evoked Release of Glutamate and the Levels of Exocytosis‐Associated Proteins in Cultured Cortical Neurons from Embryonic Rats , 1997, Journal of neurochemistry.

[6]  R. Dobrowsky,et al.  Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75 , 1996, Nature.

[7]  Howard J. Federoff,et al.  Regulated Release and Polarized Localization of Brain-Derived Neurotrophic Factor in Hippocampal Neurons , 1996, Molecular and Cellular Neuroscience.

[8]  K. Deisseroth,et al.  CREB Phosphorylation and Dephosphorylation: A Ca2+- and Stimulus Duration–Dependent Switch for Hippocampal Gene Expression , 1996, Cell.

[9]  K. Deisseroth,et al.  Signaling from Synapse to Nucleus: Postsynaptic CREB Phosphorylation during Multiple Forms of Hippocampal Synaptic Plasticity , 1996, Neuron.

[10]  B. Lu,et al.  Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus , 1996, Nature.

[11]  A. Ishida,et al.  A novel highly specific and potent inhibitor of calmodulin-dependent protein kinase II. , 1995, Biochemical and biophysical research communications.

[12]  Nancy Y. Ip,et al.  Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF , 1993, Nature.

[13]  R. Nicoll,et al.  Brain-derived neurotrophic factor (BDNF) modulates inhibitory, but not excitatory, transmission in the CA1 region of the hippocampus. , 1998, Journal of neurophysiology.

[14]  Ted Abel,et al.  Recombinant BDNF Rescues Deficits in Basal Synaptic Transmission and Hippocampal LTP in BDNF Knockout Mice , 1996, Neuron.

[15]  H. G. Kim,et al.  Neurotrophin 3 potentiates neuronal activity and inhibits gamma-aminobutyratergic synaptic transmission in cortical neurons. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Marlies Knipper,et al.  Positive Feedback between Acetylcholine and the Neurotrophins Nerve Growth Factor and Brain‐derived Neurotrophic Factor in the Rat Hippocampus , 1994, The European journal of neuroscience.

[17]  S. Cohen-Cory,et al.  BDNF Modulates, But Does Not Mediate, Activity-Dependent Branching and Remodeling of Optic Axon Arbors In Vivo , 1999, The Journal of Neuroscience.

[18]  R. Heumann,et al.  BDNF, and NT‐4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurones , 1994, Neuroreport.

[19]  H. Thoenen.  Neurotrophins and Neuronal Plasticity , 1995, Science.

[20]  L. Maffei,et al.  BDNF Regulates the Maturation of Inhibition and the Critical Period of Plasticity in Mouse Visual Cortex , 1999, Cell.

[21]  R. Malinow,et al.  Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. , 2000, Science.

[22]  Lawrence C. Katz,et al.  NT-4-mediated rescue of lateral geniculate neurons from effects of monocular deprivation , 1995, Nature.

[23]  Mu-ming Poo,et al.  Fast actions of neurotrophic factors , 1996, Current Opinion in Neurobiology.

[24]  B. Lu,et al.  Neurotrophins and hippocampal synaptic transmission and plasticity , 1999, Journal of neuroscience research.

[25]  R. Douglas Fields,et al.  Action Potential-Dependent Regulation of Gene Expression: Temporal Specificity in Ca2+, cAMP-Responsive Element Binding Proteins, and Mitogen-Activated Protein Kinase Signaling , 1997, The Journal of Neuroscience.

[26]  E. Schuman,et al.  Neurotrophins and Time: Different Roles for TrkB Signaling in Hippocampal Long-Term Potentiation , 1997, Neuron.

[27]  A. Prochiantz.  Getting hydrophilic compounds into cells: lessons from homeopeptides , 1996, Current Opinion in Neurobiology.

[28]  Mu-ming Poo,et al.  Potentiation of Developing Synapses by Postsynaptic Release of Neurotrophin-4 , 1997, Neuron.

[29]  M. Cynader,et al.  Nerve growth factor-induced ocular dominance plasticity in adult cat visual cortex. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Y. Barde,et al.  Induction of cell death by endogenous nerve growth factor through its p75 receptor , 1996, Nature.

[31]  Lawrence C. Katz,et al.  Neurotrophins regulate dendritic growth in developing visual cortex , 1995, Neuron.

[32]  L. Zhang,et al.  Impairments in High-Frequency Transmission, Synaptic Vesicle Docking, and Synaptic Protein Distribution in the Hippocampus of BDNF Knockout Mice , 1999, The Journal of Neuroscience.

[33]  Lawrence C. Katz,et al.  Opposing Roles for Endogenous BDNF and NT-3 in Regulating Cortical Dendritic Growth , 1997, Neuron.

[34]  M. Passafaro,et al.  Microtubule binding by CRIPT and its potential role in the synaptic clustering of PSD-95 , 1999, Nature Neuroscience.

[35]  I. Black,et al.  Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  L. Reichardt,et al.  Retrograde Transport of Neurotrophins from the Eye to the Brain in Chick Embryos: Roles of the p75NTR and trkB Receptors , 1996, The Journal of Neuroscience.

[37]  M. Chao,et al.  Neurotrophins: the biological paradox of survival factors eliciting apoptosis , 1998, Cell Death and Differentiation.

[38]  A. Meyer-Franke,et al.  Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture , 1995, Neuron.

[39]  W Singer,et al.  Brain‐derived Neurotrophic Factor Reverses Experience‐dependent Synaptic Modifications in Kitten Visual Cortex , 1996, The European journal of neuroscience.

[40]  C. Shatz,et al.  Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF , 1995, Science.

[41]  L Maffei,et al.  Nerve growth factor (NGF) prevents the shift in ocular dominance distribution of visual cortical neurons in monocularly deprived rats , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[42]  T Bonhoeffer,et al.  Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  L C Katz,et al.  Neurotrophins and synaptic plasticity. , 1999, Annual review of neuroscience.

[44]  M. Constantine-Paton,et al.  Patterned activity, synaptic convergence, and the NMDA receptor in developing visual pathways. , 1990, Annual review of neuroscience.

[45]  Mu-ming Poo,et al.  Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation , 1999, Nature Neuroscience.

[46]  Lawrence C Katz,et al.  Neurotrophin Regulation of Cortical Dendritic Growth Requires Activity , 1996, Neuron.

[47]  G. Stent.  A physiological mechanism for Hebb's postulate of learning. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[48]  T. Bonhoeffer.  Neurotrophins and activity-dependent development of the neocortex , 1996, Current Opinion in Neurobiology.

[49]  E. Shooter,et al.  The Regulated Secretion and Vectorial Targeting of Neurotrophins in Neuroendocrine and Epithelial Cells* , 1996, The Journal of Biological Chemistry.

[50]  B. Lu,et al.  Presynaptic Modulation of Synaptic Transmission and Plasticity by Brain-Derived Neurotrophic Factor in the Developing Hippocampus , 1998, The Journal of Neuroscience.

[51]  N. Matsuki,et al.  Inhibition of GABAA Synaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus , 1997, The Journal of Neuroscience.

[52]  B. Lu,et al.  Differential effects of GDNF and BDNF on cultured ventral mesencephalic neurons. , 1999, Brain research. Molecular brain research.

[53]  T Bonhoeffer,et al.  Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Scott E. Fraser,et al.  Effects of brain-derived neurotrophic factor on optic axon branching and remodelling in vivo , 1995, Nature.

[55]  M. Hanson,et al.  Depolarization and cAMP Elevation Rapidly Recruit TrkB to the Plasma Membrane of CNS Neurons , 1998, Neuron.