Distinct Roles for Somatically and Dendritically Synthesized Brain-Derived Neurotrophic Factor in Morphogenesis of Dendritic Spines

Abstract

, with either a short or long 3Ј untranslated region (3Ј UTR). Our previous results show that short 3Ј UTR Bdnf mRNA is restricted to cell bodies, whereas long 3Ј UTR Bdnf mRNA is also trafficked to dendrites for local translation. Mutant mice lacking long 3Ј UTR Bdnf mRNA display normal spines at 3 weeks of age, but thinner and denser spines in adults compared to wild-type littermates. These observations suggest that BDNF translated from long 3Ј UTR Bdnf mRNA, likely in dendrites, is required for spine maturation and pruning. In this study, using rat hippocampal neuronal cultures, we found that knocking down long 3Ј UTR Bdnf mRNA blocked spine head enlargement and spine elimination, whereas overexpressing long 3Ј UTR Bdnf mRNA had the opposite effect. The effect of long 3Ј UTR Bdnf mRNA on spine head enlargement and spine elimination was diminished by a human single-nucleotide polymorphism (SNP, rs712442) in its 3Ј UTR that inhibited dendritic localization of Bdnf mRNA. Furthermore, we found that overexpression of either Bdnf mRNA increased spine density at earlier time points. Spine morphological alterations were associated with corresponding changes in density, size, and function of synapses. These results indicate that somatically synthesized BDNF promotes spine formation, whereas dendritically synthesized BDNF is a key regulator of spine head growth and spine pruning.

Autophagy in synaptic development, function, and pathology

“…The time course of spine development in primary cultured hippocampal neurons is similar to that of dendritic spines in mouse brain [30,31] . In cultured neurons, the number of spines increases during 6-10 days in vitro (DIV), peaks at 14-21 DIV, and decreases after 21-28 DIV [32] .…”

Variation in the BDNF Gene Interacts With Age to Predict Mortality in a Prospective, Longitudinal Cohort with Severe TBI

“…A cumulative BDNF GRS was developed using rs6265 Met (Val/Met or Met/Met) and rs7124442 C (T/C or C/C) carrier status as hypothesized risk alleles based on the literature. 22,24 Thus, a GRS of 0 was the hypothesized no risk group (Val/Val, T/T); a GRS of 1 included carriers for 1 risk allele (Val/Val, C-carriers or Met-carriers, T/T); and a GRS of 2 included carriers of both risk alleles (Met-carriers, C-carriers).…”

“…23 Importantly, rs6265 is in linkage disequilibrium (LD) with another BDNF SNP, rs7124442. The rs7124442 variant reportedly affects neuronal BDNF mRNA trafficking 24 . While rs6265 25 and rs7124442 26 have been associated with TBI recovery, no studies have examined how these variants influence other aspects of TBI recovery, specifically mortality.…”

Brain-Derived Neurotrophic Factor Inhibits Calcium Channel Activation, Exocytosis, and Endocytosis at a Central Nerve Terminal

“…One such molecule is brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates various neuronal functions via activation of tropomyosin-related kinase B (TrkB) (Reichardt, 2006). For instance, BDNF potentiates (Kang and Schuman, 1995;Carmignoto et al, 1997) or inhibits (Tanaka et al, 1997;Frerking et al, 1998;Clark et al, 2011) synaptic transmission, enhances long-term potentiation, a cellular substrate for learning and memory (Minichiello et al, 1999), promotes synapse formation (Vicario-Abejó n et al, 1998), and changes the number and volume of dendritic spines (Orefice et al, 2013). These synaptic effects may contribute to the overall effect of BDNF on neuronal survival, differentiation, axonal branching, and dendritic growth (Huang and Reichardt, 2001;Park and Poo, 2013).…”