Wüstner Lisa-Sophie, Beuter Simone, Kriebel Martin, Volkmer Hansjürgen
NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
International Max Planck Research School, Graduate Training Centre of Neuroscience, University of Tübingen, Tübingen, Germany.
Front Mol Neurosci. 2024 Oct 24;17:1480820. doi: 10.3389/fnmol.2024.1480820. eCollection 2024.
The TrkB receptor is known for its role in regulating excitatory neuronal plasticity. However, accumulating evidence over the past decade has highlighted the involvement of TrkB in regulating inhibitory synapse stability and plasticity, particularly through regulation of the inhibitory scaffold protein gephyrin, although with contradicting results.
In this study, we extended on these findings by overexpressing rat TrkB mutants deficient in either Shc-or PLCγ-dependent signaling, as well as a kinase-dead mutant, to dissect the contributions of specific TrkB-dependent signaling pathways to gephyrin clustering.
Our results demonstrate that TrkB signaling is required for gephyrin clustering on the perisomatic area of granule cells in the dentate gyrus . To further investigate, we expressed TrkB wild-type and mutants in hippocampal neurons .
Under basal conditions, TrkB-Shc signaling was important for the reduction of gephyrin cluster size, while TrkB-PLCγ signaling accounts for gephyrin clustering specifically at synaptic sites. Concomitant, impaired PLCγ signaling was associated with disinhibition of transduced neurons. Moreover, chemically induced inhibitory long-term potentiation (chem iLTP) depended on TrkB signaling and the activation of both Shc and PLCγ pathways.
Our findings suggest a complex, pathway-specific regulation of TrkB-dependent gephyrin clustering, both under basal conditions and during chem iLTP.
TrkB受体因其在调节兴奋性神经元可塑性方面的作用而闻名。然而，在过去十年中，越来越多的证据表明TrkB参与调节抑制性突触的稳定性和可塑性，特别是通过调节抑制性支架蛋白桥连蛋白，尽管结果相互矛盾。
在本研究中，我们通过过表达缺乏Shc或PLCγ依赖性信号传导的大鼠TrkB突变体以及激酶失活突变体，扩展了这些发现，以剖析特定TrkB依赖性信号传导途径对桥连蛋白聚集的贡献。
我们的结果表明，TrkB信号传导是齿状回颗粒细胞体周区域桥连蛋白聚集所必需的。为了进一步研究，我们在海马神经元中表达了TrkB野生型和突变体。
在基础条件下，TrkB-Shc信号传导对于减小桥连蛋白簇大小很重要，而TrkB-PLCγ信号传导则专门负责突触部位的桥连蛋白聚集。同时，PLCγ信号传导受损与转导神经元的去抑制有关。此外，化学诱导的抑制性长时程增强（chem iLTP）依赖于TrkB信号传导以及Shc和PLCγ途径的激活。
我们的研究结果表明，在基础条件下和chem iLTP期间，TrkB依赖性桥连蛋白聚集存在复杂的、途径特异性的调节。
