Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice.
Brain-derived neurotrophic factor (BDNF) promotes long-term potentiation (LTP) at hippocampal CA1 synapses by a presynaptic enhancement of synaptic transmission during high-frequency stimulation (HFS). Here we have investigated the mechanisms of BDNF action using two lines of BDNF knockout mice. Among other presynaptic impairments, the mutant mice exhibited more pronounced synaptic fatigue at CA1 synapses during high-frequency stimulation, compared with wild-type animals. Quantitative analysis of CA1 synapses revealed a significant reduction in the number of vesicles docked at presynaptic active zones in the mutant mice. Synaptosomes prepared from the mutant hippocampus exhibited a marked decrease in the levels of synaptophysin as well as synaptobrevin [vesicle-associated membrane protein (VAMP-2)], a protein known to be involved in vesicle docking and fusion. Treatment of the mutant slices with BDNF reversed the electrophysiological and biochemical deficits in the hippocampal synapses. Taken together, these results suggest a novel role for BDNF in the mobilization and/or docking of synaptic vesicles to presynaptic active zones.
Pozzo-Miller
L D
LD
Laboratory of Neurobiology, National Institute of Neurological Diseases and Stroke (NINDS), National Institutes of Health, Bethesda, Maryland 20892, USA.
Gottschalk
W
W
Zhang
L
L
McDermott
K
K
Du
J
J
Gopalakrishnan
R
R
Oho
C
C
Sheng
Z H
ZH
Lu
B
B
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D017729:Presynaptic Terminals / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D050683:R-SNARE Proteins; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D016708:Synaptophysin / Q000032:analysis / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25; D050857:Synaptotagmins; D050827:Syntaxin 1
D000954:Antigens, Surface; D019208:Brain-Derived Neurotrophic Factor; D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D050683:R-SNARE Proteins; C494209:Snap25 protein, mouse; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D050857:Synaptotagmins; D002118:Calcium