Lisa-Sophie Wüstner ^1,2 Simone Beuter ¹ Martin Kriebel ¹ Hansjürgen Volkmer ^1,2*

• ¹ NMI at the University of Tübingen, Reutlingen, Baden-Württemberg, Germany
• ² Graduate Training Centre of Neuroscience, International Max Planck Research School, University of Tübingen, Tübingen, Baden-Württemberg, Germany

The TrkB receptor is known for its role in regulating neuronal excitatory plasticity. Over the past decade, accumulating evidence 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 investigate the contributions of different TrkB-dependent signaling pathways to gephyrin clustering. Based on our findings that TtrkB signaling is required for gephyrin clustering on the somata of granule cell bodies in the dentate gyrus in vivo, we expressed TrkB wild type and TrkB mutants in hippocampal neurons. Under basal conditions, TrkB-Shc signaling was important for the reduction of gephyrin cluster size while TrkB-PLC signaling accounts for increased gephyrin clustering at synaptic sites. Impaired PLC signaling is associated with decreased clustering of GABAA receptor subunit 2 and disinhibition of principal neurons. Moreover, chemically induced inhibitory long-term potentiation (chem iLTP) depends on TrkB signaling and the activation of both Shc and PLC pathways. Our findings suggest a complex regulation of TrkB-dependent gephyrin clustering under basal conditions and after chem iLTP.