Mechanism of TrkB-mediated hippocampal long-term potentiation.
The TrkB receptor tyrosine kinase and its ligand, BDNF, have an essential role in certain forms of synaptic plasticity. However, the downstream pathways required to mediate these functions are unknown. We have studied mice with a targeted mutation in either the Shc or the phospholipase Cgamma (PLCgamma) docking sites of TrkB (trkB(SHC/SHC) and trkB(PLC/PLC) mice). We found that hippocampal long-term potentiation was impaired in trkB(PLC/PLC) mice, but not trkB(SHC/SHC) mice. BDNF stimulation of primary neurons derived from trkB(PLC/PLC) mice fully retained their ability to activate MAP kinases, whereas induction of CREB and CaMKIV phosphorylation was strongly impaired. The opposite effect was observed in trkB(SHC/SHC) neurons, suggesting that MAPKs and CREB act in parallel pathways. Our results provide genetic evidence that TrkB mediates hippocampal plasticity via recruitment of PLCgamma, and by subsequent phosphorylation of CaMKIV and CREB.
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D005333:Fetus; D006624:Hippocampus / Q000002:abnormalities / Q000166:cytology / Q000378:metabolism*; D017874:Immediate-Early Proteins; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics; D017774:Long-Term Potentiation / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051966:Phospholipase C gamma; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000235:genetics; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors / Q000235:genetics; D010738:Type C Phospholipases / Q000172:deficiency* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors; D020813:Receptor, trkB; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma