Duarte-Ruiz, M.; Moreno-Castillo, A.; El Yousfi, Y.; Moreno-Castro, C.; Martinez-Martinez, N.; Jimenez-Lozano, S.; Kennel, M.; Ruiz-Rodriguez, C.; Rodriguez-Caparros, A.; Lopez-Ros, J.; de la Grange, P.; Hernandez-Munain, C.; Sune, C.

BDNF signaling through its receptor TRKB plays a critical role in brain development, neuroplasticity and homeostasis. Alternative splicing of the TRKB gene, NTRK2, generates either the full-length receptor (TRKB-FL) or a truncated isoform (TRKB-T1) that inhibits BDNF signaling and has been implicated in neurodegenerative diseases, psychiatric disorders and cognitive impairments. Here, we show that PRPF40B, a splicing factor associated with neuronal dysfunction, promotes production of the TRKB-FL isoform during neuronal differentiation. Silencing PRPF40B increases TRKB-T1 expression, impairing expression of genes important for neuronal differentiation and synaptic plasticity. Our data thus identify PRPF40B as a key regulator of the balance between TRKB receptor isoforms, crucial for fine-tuning neuronal responses and for preventing neuroplasticity or survival impairments, providing also a mechanism for the role of PRPF40B in the pathogenesis of various human neurodegenerative diseases and psychiatric disorders