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 Cγ (PLCγ) docking sites of TrkB (trkBSHC/SHC and trkBPLC/PLC mice). We found that hippocampal long-term potentiation was impaired in trkBPLC/PLC mice, but not trkBSHC/SHC mice. BDNF stimulation of primary neurons derived from trkBPLC/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 trkBSHC/SHC neurons, suggesting that MAPKs and CREB act in parallel pathways. Our results provide genetic evidence that TrkB mediates hippocampal plasticity via recruitment of PLCγ, and by subsequent phosphorylation of CaMKIV and CREB.