Brain-derived neurotrophic factor triggers transcription-dependent, late phase long-term potentiation in vivo.
Acute intrahippocampal infusion of brain-derived neurotrophic factor (BDNF) leads to long-term potentiation (BDNF-LTP) of synaptic transmission at medial perforant path-->granule cell synapses in the rat dentate gyrus. Endogenous BDNF is implicated in the maintenance of high-frequency stimulation-induced LTP (HFS-LTP). However, the relationship between exogenous BDNF-LTP and HFS-LTP is unclear. First, we found that BDNF-LTP, like HFS-LTP, is associated with enhancement in both synaptic strength and granule cell excitability (EPSP-spike coupling). Second, treatment with a competitive NMDA receptor (NMDAR) antagonist blocked HFS-LTP but had no effect on the development or magnitude of BDNF-LTP. Thus, NMDAR activation is not required for the induction or expression of BDNF-LTP. Formation of stable, late phase HFS-LTP requires mRNA synthesis and is coupled to upregulation of the immediate early gene activity-regulated cytoskeleton-associated protein (Arc). Local infusion of the transcription inhibitor actinomycin D (ACD) 1 hr before or immediately before BDNF infusion inhibited BDNF-LTP and upregulation of Arc protein expression. ACD applied 2 hr after BDNF infusion had no effect, defining a critical time window of transcription-dependent synaptic strengthening. Finally, the functional role of BDNF-LTP was assessed in occlusion experiments with HFS-LTP. HFS-LTP was induced, and BDNF was infused at time points corresponding to early phase (1 hr) or late phase (4 hr) HFS-LTP. BDNF applied during the early phase led to normal BDNF-LTP. In contrast, BDNF-LTP was completely occluded during the late phase. The results strongly support a role for BDNF in triggering transcription-dependent, late phase LTP in the intact adult brain.
Department of Physiology and Locus on Neuroscience, University of Bergen, N-5009 Bergen, Norway.
Elhoucine
E
Messaoudi
Shui-Wang
SW
Ying
Tambudzai
T
Kanhema
Susan D
SD
Croll
Clive R
CR
Bramham
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000493:pharmacokinetics / Q000494:pharmacology*; D003598:Cytoskeletal Proteins; D004333:Drug Administration Routes; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D017874:Immediate-Early Proteins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014018:Tissue Distribution; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D003598:Cytoskeletal Proteins; D018691:Excitatory Amino Acid Antagonists; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; C092069:activity regulated cytoskeletal-associated protein