Distinct effects on the dendritic arbor occur by microbead versus bath administration of brain-derived neurotrophic factor

Abstract

Proper communication among neurons depends on an appropriately formed dendritic arbor, and thus, aberrant changes to the arbor are implicated in many pathologies, ranging from cognitive disorders to neurodegenerative diseases. Due to the importance of dendritic shape to neuronal network function, the morphology of dendrites is tightly controlled and is influenced by both intrinsic and extrinsic factors. In this work, we examine how brain-derived neurotrophic factor (BDNF), one of the most well-studied extrinsic regulators of dendritic branching, affects the arbor when it is applied locally via microbeads to cultures of hippocampal neurons. We found that local application of BDNF increases both proximal and distal branching in a time-dependent manner and that local BDNF application attenuated pruning of dendrites that occurs with neuronal maturation. Additionally, we examined whether cytosolic PSD-95 interactor (cypin), an intrinsic regulator of dendritic branching, plays a role in these changes and found strong evidence for the involvement of cypin in BDNF-promoted increases in dendrites after 24 but not 48 hours of application. This current study extends our previous work in which we found that bath application of BDNF for 72 hours, but not shorter times, increases proximal dendrite branching and that this increase occurs through transcriptional regulation of cypin. Moreover, this current work illustrates how dendritic branching is regulated differently by the same growth factor depending on its spatial localization, suggesting a novel pathway for modulation of dendritic branching locally.

Antidepression action of BDNF requires and is mimicked by Gαi1/3 expression in the hippocampus

“…It is possible Gαi1/3 proteins play a role in TrkB sorting into distinct endosomal compartments essential for the activation of specific signaling cascades that modulate synapse formation and survival and the differentiation of neurons in the CNS. BDNF is a key mediator of activity-dependent dendrite formation (43,44) via PI3K and MAPK signaling (45). In support of the role for Gαi1/3 in BDNF signaling, Gαi1/3 knockdown in hippocampal neurons in vitro (Fig.…”

The 3′ UTRs of Brain-Derived Neurotrophic Factor Transcripts Differentially Regulate the Dendritic Arbor

“…Dendrites were assessed as previously described ( Kutzing et al, 2010 ; Langhammer et al, 2010 ; Kwon et al, 2011 ; O’Neill et al, 2017 ) using the most common Sholl analysis, the Inside-Out labeling scheme ( O’Neill et al, 2015 ). We used the “Bonfire” program developed by our laboratory to perform semi-automated Sholl analysis with a 6 μm ring interval starting at 0 μm from the soma.…”

“…Brain-derived neurotrophic factor (BDNF) is a well-known regulator of dendrite morphology ( McAllister et al, 1995 , 1996 ; Baker et al, 1998 ; Horch et al, 1999 ; Jin et al, 2003 ; Segal, 2003 ; Dijkhuizen and Ghosh, 2005 ; Choi et al, 2009 ; Gao et al, 2009 ; Kuczewski et al, 2009 ; Alder et al, 2012 ; Lazo et al, 2013 ; Park and Poo, 2013 ). Previously, our laboratory reported that BDNF alters the dendritic arbor uniquely depending on how it is applied ( Kwon et al, 2011 ; O’Neill et al, 2017 ). In this work, we extend our previous studies by probing how overexpression and intracellular transport and targeting of BDNF mRNA affect dendritogenesis during the active branching period ( Cline, 2001 ; Wong and Ghosh, 2002 ; Charych et al, 2006 ).…”

“…This work explores the changes that occur to the dendritic arbor of hippocampal neurons as a result of overexpressing BDNF transcripts containing different length 3′ UTRs. We overexpressed BDNF mRNA from day in vitro (DIV) 7–10 as we had done previously for extracellular BDNF application experiments ( Kwon et al, 2011 ; O’Neill et al, 2017 ), and we consider the results of this study in context with our previous work. We found that the 3′ UTR, and hence intracellular transport and targeting, of BDNF mRNA affects the spatial arrangement of and the number and length of dendrites.…”

The many disguises of the signalling endosome

“…Internalisation of receptors is crucial not only for long distance propagation of neurotrophic effects, but also for engaging intracellular interactors enabling the activation of distinct signalling pathways [15,124]. It is critical for local effects relying on the accumulation of signalling molecules at specific locations, as in the case of synaptic assembly sites, branching points on neurites and the leading edge of a migrating precursor [51,53,84,85,125]. Specific mechanisms of internalisation have proved to be particularly important for generating intracellular compartments with distinct signalling capabilities.…”