proBDNF Negatively Regulates Neuronal Remodeling, Synaptic Transmission, and Synaptic Plasticity in Hippocampus

Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75NTR. In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75NTR. Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF. [Display omitted] •A cleavage-resistant proBDNF knockin mouse probes role of proBDNF•Results are distinct from bdnf+/− mice and define proBDNF-specific effects•ProBDNF impairs dendritic structure, basal transmission, and LTP but enhances LTD Postnatal formation of synaptic connections is highly regulated, and BDNF has been postulated to be involved in this process. Here, Yang et al. demonstrate that proBDNF is expressed during postnatal development and evaluate its actions on hippocampal structure and synaptic plasticity in a probdnf knockin mouse. Endogenously expressed proBDNF reduces dendritic arbors and spine density and alters synaptic plasticity. These data suggest that proBDNF is a key regulator shaping neural circuitry and synaptic plasticity.