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Published online 18 September 2000. doi:10.1083/jcb.150.6.1423
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© The Rockefeller University Press, 0021-9525/2000//1423 $5.00
The Journal of Cell Biology, Volume 150, Number 6, , 2000 1423-1434

Original Article

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



Jing Dua, Linyin Fengb, Feng Yanga, and Bai Lua

a Unit on Synapse Development and Plasticity, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4480
b Institutes of Neuroscience, Shanghai, China 200031
Unit on Synapse Development and Plasticity, NICHD, NIH, Bldg. 49, Rm. 5A38, 49 Convent Dr., Bethesda, MD 20892-4480.(301) 496-9939(301) 435-2970

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.

Key Words: TrkB receptors • tetanic stimulation • calcium influx • Ca2+/calmodulin-dependent kinase II • synaptic transmission

© 2000 The Rockefeller University Press

Abbreviations used in this paper: AIP, autocamtide-2-related inhibitory peptide; BDNF, brain-derived neurotrophic factor; CaMKII, Ca2+/calmodulin-dependent kinase II; CNS, central nervous system; CNQX, 6-cyano-7-nitroquinozaline-2,3-dione; kyn, kynurenic acid; LTD, long-term depression; LTP, long-term potentiation; p75NR, low affinity receptor p75; TBS, theta burst stimulation; TTX, tetrodotoxin.


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