Reduced number of functional glutamatergic synapses in hippocampal neurons overexpressing full-length TrkB receptors.
Brain-derived neurotrophic factor (BDNF) acutely modulates the efficacy of central glutamatergic synapses via activation of the receptor tyrosine kinase TrkB. On a longer time scale, recent evidence suggests an additional role of TrkB signaling in the formation of excitatory synaptic connections. Here, we have overexpressed full-length TrkB receptors (fl-TrkB) in hippocampal neurons, to investigate the contribution of BDNF signaling to the maturation of glutamatergic synapses. Using patch clamp recordings, we show a three-fold reduction in glutamatergic excitatory autaptic and synaptic current amplitudes in neurons overexpressing fl-TrkB, and application of saturating concentrations of BDNF and NT-4/5 completely reverses this effect. Compatible with these overexpression data, in untransfected neurons, scavenging of endogenous BDNF and NT-4/5 by TrkB-IgGs reduces excitatory autaptic current (EAC) amplitudes. By overexpression of truncated TrkB receptors (TrkB.T1, TrkB.T2) and a chimeric receptor containing only the intracellular domain of fl-TrkB, we show that intra- and extracellular domains of fl-TrkB are necessary to observe the EAC reduction. Labeling of presynaptic terminals with FM 4-64 revealed, that the reduced EAC amplitudes in fl-TrkB overexpressing neurons are accompanied by a two-fold reduction in synapse number. These results suggest, that ligand-independent signaling through fl-TrkB receptors can decrease glutamatergic synaptic strength, if sufficient amounts of BDNF or NT-4/5 are not available.
Klau
M
M
Department of Molecular Neurobiochemistry, Ruhr-University Bochum, Bochum, Germany.
Hartmann
M
M
Erdmann
K S
KS
Heumann
R
R
Lessmann
V
V
D000375:Aging / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005456:Fluorescent Dyes; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D051381:Rats; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; C092350:FM 4-64; D005456:Fluorescent Dyes; D009414:Nerve Growth Factors; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D018698:Glutamic Acid; D020813:Receptor, trkB; C073922:neurotrophin 4