Requirements of Postnatal proBDNF in the Hippocampus for Spatial Memory Consolidation and Neural Function.

Wei Sun,Hong Cheng,Yang Yang,Xiaolian Li,Lei An,Dongxin Tang

doi:10.3389/fcell.2021.678182

Abstract

Mature brain-derived neurotrophic factor (BDNF) and its downstream signaling pathways have been implicated in regulating postnatal development and functioning of rodent brain. However, the biological role of its precursor pro-brain-derived neurotrophic factor (proBDNF) in the postnatal brain remains unknown. The expression of hippocampal proBDNF was blocked in postnatal weeks, and multiple behavioral tests, Western blot and morphological techniques, and neural recordings were employed to investigate how proBDNF played a role in spatial cognition in adults. The peak expression and its crucial effects were found in the fourth but not in the second or eighth postnatal week. Blocking proBDNF expression disrupted spatial memory consolidation rather than learning or memory retrieval. Structurally, blocking proBDNF led to the reduction in spine density and proportion of mature spines. Although blocking proBDNF did not affect N-methyl-D-aspartate (NMDA) receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, the learning-induced phosphorylation of the GluN2B subunit level declined significantly. Functionally, paired-pulse facilitation, post-low-frequency stimulation (LFS) transiently enhanced depression, and GluN2B-dependent short-lasting long-term depression in the Schaffer collateral-CA1 pathway were weakened. The firing rate of pyramidal neurons was significantly suppressed around the target region during the memory test. Furthermore, the activation of GluN2B-mediated signaling could effectively facilitate neural function and mitigate memory impairment. The findings were consistent with the hypothesis that postnatal proBDNF played an essential role in synaptic and cognitive functions.

Highlights

Mature brain-derived neurotrophic factor plays an important role in neural circuit formation (Fernandes et al, 2015; Li et al, 2019), which is a critical step in aiding in hippocampus (HPC)-dependent memory in adolescents and adults (Lu et al, 2014; Itoh et al, 2016)
To confirm if infusion of anti-pro-brain-derived neurotrophic factor (proBDNF) antibody affects the level of proBDNF or its receptor, p75NTR, we assessed their levels at PD56
Hippocampal proBDNF was not disrupted by postnatal blockage at PD2w or PD4w (Figure 2C; one-way ANOVA, effect of treatment: F(2,15) = 0.22, p > 0.05), neither did the p75NTR (Figure 2D; effect of treatment: F(2,15) = 0.29, p > 0.05)

Summary

Introduction

Mature brain-derived neurotrophic factor (mBDNF) plays an important role in neural circuit formation (Fernandes et al, 2015; Li et al, 2019), which is a critical step in aiding in hippocampus (HPC)-dependent memory in adolescents and adults (Lu et al, 2014; Itoh et al, 2016). Different effects were observed in dorsal hippocampal regions involved in learning and memory and ventral regions involved in fear and anxietylike behavior Both mBDNF and proBDNF are secreted in adulthood, but the highest levels of proBDNF are observed perinatally (Yang J. et al, 2009). NMDARs may be important mediators of proBDNF-induced defects in neurodevelopment and neurocognition

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