The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity

Abstract

The fine tuning of neural networks during development and learning relies upon both functional and structural plastic processes. Changes in the number as well as in the size and shape of dendritic spines are associated to long-term activity-dependent synaptic plasticity. However, the molecular mechanisms translating functional into structural changes are still largely unknown. In this context, neurotrophins, like Brain-Derived Neurotrophic Factor (BDNF), are among promising candidates. Specifically BDNF-TrkB receptor signaling is crucial for activity-dependent strengthening of synapses in different brain regions. BDNF application has been shown to positively modulate dendritic and spine architecture in cortical and hippocampal neurons as well as structural plasticity in vitro. However, a global BDNF deprivation throughout the central nervous system (CNS) resulted in very mild structural alterations of dendritic spines, questioning the relevance of the endogenous BDNF signaling in modulating the development and the mature structure of neurons in vivo. Here we show that a loss-of-function approach, blocking BDNF results in a significant reduction in dendritic spine density, associated with an increase in spine length and a decrease in head width. These changes are associated with a decrease in F-actin levels within spine heads. On the other hand, a gain-of-function approach, applying exogenous BDNF, could not reproduce the increase in spine density or the changes in spine morphology previously described. Taken together, we show here that the effects exerted by BDNF on the dendritic architecture of hippocampal neurons are dependent on the neuron's maturation stage. Indeed, in mature hippocampal neurons in vitro as shown in vivo BDNF is specifically required for the activity-dependent maintenance of the mature spine phenotype.

Protein Kinase Cϵ (PKCϵ) Promotes Synaptogenesis through Membrane Accumulation of the Postsynaptic Density Protein PSD-95

“…HuD increases as a result of PKC⑀ activation after learning (67) and stabilizes the mRNA for BDNF, nerve growth factor (NGF), and neurotrophin-3 (NT-3) (19). PKC⑀ activation induces the synthesis of BDNF (10,20,47), and BDNF induces transport of PSD-95 to the dendrites (68), which is required for maintenance of mature spines (69). Deficits of PKC⑀ function could also contribute to the synapse loss in Alzheimer disease (15), whereas the therapeutic elimination of such deficits may offer a strategy for the treatment of synaptic loss in Alzheimer disease and other synaptic disorders.…”

Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors

“…Among the mRNAs that are translated in dendrites, brain-derived neurotrophic factor (BDNF) is of particular interest for its implication in development, cell survival and plasticity of the nervous system. Growing evidence indicates that local protein synthesis of BDNF is a key event for an extensive reorganization of dendrite arborization and spine morphology Baj et al, 2011;Kellner et al, 2014;Sun et al, 2014;Verpelli et al, 2010;Xu et al, 2014). Translation of neuronal mRNAs localized in dendrites is controlled by signaling cascades activated by glutamate receptors and BDNF itself (Bramham and Wells, 2007;Leal et al, 2014).…”

BDNF over-expression increases olfactory bulb granule cell dendritic spine density in vivo

“…In vivo, BDNF over-expression in the adult TgBDNF hippocampus increases spine density on CA1 pyramidal cells, while conditional ablation of BDNF promotes a shift to longer, thinner spines, with no change in density (An et al, 2008; Rauskolb et al, 2010). Blocking endogenous BDNF in vitro similarly increases the prevalence of longer, thinner, immature spines in pyramidal cells, but also reduces spine density (Kellner et al, 2014). Treatment with exogenous BDNF has little effect on dendritic morphology of mature pyramidal cells, but immature cells respond with enhanced dendritic branching (Kellner et al, 2014).…”

“…Blocking endogenous BDNF in vitro similarly increases the prevalence of longer, thinner, immature spines in pyramidal cells, but also reduces spine density (Kellner et al, 2014). Treatment with exogenous BDNF has little effect on dendritic morphology of mature pyramidal cells, but immature cells respond with enhanced dendritic branching (Kellner et al, 2014). Spine density in mature cells can be decreased by suppressing activity in vitro, and TrkB-IgG treatment reduces density further.…”