Global Deprivation of Brain-Derived Neurotrophic Factor in the CNS Reveals an Area-Specific Requirement for Dendritic Growth

Abstract

Although brain-derived neurotrophic factor (BDNF) is linked with an increasing number of conditions causing brain dysfunction, its rolein the postnatal CNS has remained difficult to assess. This is because the bdnf-null mutation causes the death of the animals before BDNF levels have reached adult levels. In addition, the anterograde axonal transport of BDNF complicates the interpretation of area-specific gene deletion. The present study describes the generation of a new conditional mouse mutant essentially lacking BDNF throughout the CNS. It shows that BDNF is not essential for prolonged postnatal survival, but that the behavior of such mutant animals is markedly altered. It also reveals that BDNF is not a major survival factor for most CNS neurons and for myelination of their axons. However, it is required for the postnatal growth of the striatum, and single-cell analyses revealed a marked decreased in dendritic complexity and spine density. In contrast, BDNF is dispensable for the growth of the hippocampus and only minimal changes were observed in the dendrites of CA1 pyramidal neurons in mutant animals. Spine density remained unchanged, whereas the proportion of the mushroom-type spine was moderately decreased. In line with these in vivo observations, we found that BDNF markedly promotes the growth of cultured striatal neurons and of their dendrites, but not of those of hippocampal neurons, suggesting that the differential responsiveness to BDNF is part of a neuron-intrinsic program.

Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments

“…4D), suggesting that limiting amounts of these transcripts might regulate plasticity of distal dendrites into adulthood. A study of conditional bdnf KO adult mice found a significant decrease in dendritic complexity and number of mushroom spines on distal apical dendrites of hippocampal neurons (33). This finding can be reconciled by our data showing that only distal, secondary dendrites, but not proximal dendrites, on mature neurons (Fig.…”

Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome

“…This mouse model is all the more relevant because parallels have previously been noted between the phenotypes of Bdnf conditional mutations and mice lacking Mecp2, including decreased motor activity, obesity in female animals, and hind-limb clasping (13,15). At the morphological level, the lack of BDNF severely impacts the development of GABAergic neurons in the striatum (15,35), which may in part explain the clasping phenotype. The striatum consists mainly of GABAergic neurons that seem to be particularly dependent on BDNF, not for their survival in the postnatal weeks but for their growth and arborization (15,35).…”

“…At the morphological level, the lack of BDNF severely impacts the development of GABAergic neurons in the striatum (15,35), which may in part explain the clasping phenotype. The striatum consists mainly of GABAergic neurons that seem to be particularly dependent on BDNF, not for their survival in the postnatal weeks but for their growth and arborization (15,35). As is the case with Bdnf conditional mutations (15), the striatum of Mecp2 −/y animals is ∼30% smaller than wild-type controls at ∼1 mo of age (36).…”

“…Given this background, mice lacking MeCP2 represent an attractive model to test substances that may increase the levels of BDNF and improve some of their symptoms, such as reduced and impaired motor behavior (13). In addition, similarities have been noted between mice lacking MeCP2 and BDNF in neurons, such as a hind-limb clasping phenotype, obesity in females, and an anxiety type of behavior (15).…”

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“…La découverte de molécules structurellement semblables au NGF, en particulier du BDNF qui est la neurotrophine de loin la plus abondante dans le SNC [5], a contribué à renforcer l'hypothèse selon laquelle les mécanis-mes contrôlant la survie des neurones dans le SNC pourraient être similaires à ceux opérant dans le SNP. Cependant, un nombre croissant d'observations ont montré de plus en plus clairement que même en l'absence complète de BDNF ou d'autres facteurs de croissance, le SNC se développe sans perte massive de neurones [6].…”