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Functional evidence that BDNF is an anterograde neuronal trophic factor in the CNS.

ABSTRACT: In this report, we have tested the hypothesis that brain-derived neurotrophic factor (BDNF) is an anterograde neurotrophic factor in the CNS and have focused on central noradrenergic neurons that synthesize BDNF. Double-label immunocytochemistry for BDNF and dopamine-beta-hydroxylase (DBH), a marker for noradrenergic neurons, demonstrated that BDNF is partially localized to noradrenergic nerve fibers and terminals in the adult rat brain. To test the functional importance of this anterograde BDNF, we analyzed transgenic mice carrying a DBH-BDNF minigene. Increased synthesis of BDNF in noradrenergic neurons of DBH-BDNF mice caused elevated TrkB tyrosine kinase activation throughout postnatal life in the neocortex, a noradrenergic target region. This afferently regulated increase in TrkB receptor activity led to long-lasting alterations in cortical morphology. To determine whether noradrenergic neuron-expressed BDNF also anterogradely regulated neuronal survival, we examined a second noradrenergic target, neonatal facial motoneurons. One week after axotomy, 72% of facial motoneurons were lost in control animals, whereas only 30-35% were lost in DBH-BDNF transgenic mice. Altogether, these results indicate that BDNF is anterogradely transported to fibers and terminals of noradrenergic neurons, that anterogradely secreted BDNF causes activation of TrkB in target regions, and that this secretion has functional consequences for target neuron survival and differentiation. This presynaptic secretion of BDNF may provide a cellular mechanism for modulating neural circuitry, in either the developing or mature nervous system.

SUBMITTER: Fawcett JP

PROVIDER: S-EPMC6792589 | biostudies-literature | 1998 Apr

REPOSITORIES: biostudies-literature

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Functional evidence that BDNF is an anterograde neuronal trophic factor in the CNS.

Fawcett J P JP Bamji S X SX Causing C G CG Aloyz R R Ase A R AR Reader T A TA McLean J H JH Miller F D FD

The Journal of neuroscience : the official journal of the Society for Neuroscience 19980401 8

In this report, we have tested the hypothesis that brain-derived neurotrophic factor (BDNF) is an anterograde neurotrophic factor in the CNS and have focused on central noradrenergic neurons that synthesize BDNF. Double-label immunocytochemistry for BDNF and dopamine-beta-hydroxylase (DBH), a marker for noradrenergic neurons, demonstrated that BDNF is partially localized to noradrenergic nerve fibers and terminals in the adult rat brain. To test the functional importance of this anterograde BDNF ...[more]

PMID: 9525998

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Project description:In multiple sclerosis, microstructural damage of normal-appearing brain tissue is an important feature of its pathology. Understanding these mechanisms is vital to help develop neuroprotective strategies. The visual pathway is a key model to study mechanisms of damage and recovery in demyelination. Anterograde trans-synaptic degeneration across the lateral geniculate nuclei has been suggested as a mechanism of tissue damage to explain optic radiation abnormalities seen in association with demyelinating disease and optic neuritis, although evidence for this has relied solely on cross-sectional studies. We therefore aimed to assess: (i) longitudinal changes in the diffusion properties of optic radiations after optic neuritis suggesting trans-synaptic degeneration; (ii) the predictive value of early optic nerve magnetic resonance imaging measures for late optic radiations changes; and (iii) the impact on visual outcome of both optic nerve and brain post-optic neuritis changes. Twenty-eight consecutive patients with acute optic neuritis and eight healthy controls were assessed visually (logMAR, colour vision, and Sloan 1.25%, 5%, 25%) and by magnetic resonance imaging, at baseline, 3, 6, and 12 months. Magnetic resonance imaging sequences performed (and metrics obtained) were: (i) optic nerve fluid-attenuated inversion-recovery (optic nerve cross-sectional area); (ii) optic nerve proton density fast spin-echo (optic nerve proton density-lesion length); (iii) optic nerve post-gadolinium T1-weighted (Gd-enhanced lesion length); and (iv) brain diffusion-weighted imaging (to derive optic radiation fractional anisotropy, radial diffusivity, and axial diffusivity). Mixed-effects and multivariate regression models were performed, adjusting for age, gender, and optic radiation lesion load. These identified changes over time and associations between early optic nerve measures and 1-year global optic radiation/clinical measures. The fractional anisotropy in patients' optic radiations decreased (P = 0.018) and radial diffusivity increased (P = 0.002) over 1 year following optic neuritis, whereas optic radiation measures were unchanged in controls. Also, smaller cross-sectional areas of affected optic nerves at 3 months post-optic neuritis predicted lower fractional anisotropy and higher radial diffusivity at 1 year (P = 0.007) in the optic radiations, whereas none of the inflammatory measures of the optic nerve predicted changes in optic radiations. Finally, greater Gd-enhanced lesion length at baseline and greater optic nerve proton density-lesion length at 1 year were associated with worse visual function at 1 year (P = 0.034 for both). Neither the cross-sectional area of the affected optic nerve after optic neuritis nor the damage in optic radiations was associated with 1-year visual outcome. Our longitudinal study shows that, after optic neuritis, there is progressive damage to the optic radiations, greater in patients with early residual optic nerve atrophy, even after adjusting for optic radiation lesions. These findings provide evidence for trans-synaptic degeneration.

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Functional evidence that BDNF is an anterograde neuronal trophic factor in the CNS.

Publications

Functional evidence that BDNF is an anterograde neuronal trophic factor in the CNS.

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