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Mechanism of TrkB-mediated hippocampal long-term potentiation
Liliana Minichiello1, Anna Maria Calella, Diego L Medina
1European Molecular Biology Laboratory, via Ramarini 32, 00016, Monterotondo, Italy. mini@embl-monterotondo.it
Abstract:
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.
Insights
Brain-derived neurotrophic factor (BDNF) signaling through TrkB receptors is vital for synaptic plasticity. Genetic studies reveal phospholipase Cgamma (PLCγ) recruitment by TrkB is essential for hippocampal long-term potentiation.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Signaling
Background:
- The TrkB receptor tyrosine kinase and its ligand, BDNF, play crucial roles in synaptic plasticity.
- Downstream signaling pathways mediating TrkB functions in synaptic plasticity remain largely uncharacterized.
Purpose of the Study:
- To elucidate the specific downstream pathways of TrkB essential for hippocampal synaptic plasticity.
- To investigate the roles of Shc and phospholipase Cgamma (PLCγ) docking sites in TrkB-mediated signaling.
Main Methods:
- Utilized genetically modified mice with targeted mutations in TrkB docking sites: trkB(SHC/SHC) and trkB(PLC/PLC).
- Assessed hippocampal long-term potentiation (LTP) in these mouse models.
- Stimulated primary neurons from mutant mice and analyzed the phosphorylation of key signaling molecules, including MAP kinases, CREB, and CaMKIV.
Main Results:
- Hippocampal LTP was significantly impaired in trkB(PLC/PLC) mice, but not in trkB(SHC/SHC) mice.
- Neurons from trkB(PLC/PLC) mice showed normal MAP kinase activation but impaired CREB and CaMKIV phosphorylation upon BDNF stimulation.
- Conversely, trkB(SHC/SHC) neurons exhibited impaired MAP kinase activation, suggesting parallel signaling pathways.
Conclusions:
- TrkB receptor mediates hippocampal plasticity through the recruitment of PLCγ.
- Subsequent phosphorylation of CaMKIV and CREB by PLCγ is critical for TrkB-dependent synaptic plasticity.
- MAPK and CREB signaling pathways function in parallel downstream of TrkB.