Patterns of expression of brain-derived neurotrophic factor and tyrosine kinase B mRNAs and distribution and ultrastructural localization of their proteins in the visual pathway of the adult rat

doi:10.1016/j.neuroscience.2006.02.056

Neuroscience

Volume 140, Issue 3, 2006, Pages 913-928

https://doi.org/10.1016/j.neuroscience.2006.02.056 Get rights and content

Abstract

We have examined the cellular and subcellular distribution and the patterns of expression of brain-derived neurotrophic factor (BDNF), and of its high affinity receptor, tyrosine kinase B (TrkB), in retinorecipient regions of the brain, including the superior colliculus, the lateral geniculate nucleus and the olivary pretectal nucleus. In the retinorecipient layers of the superior colliculus, BDNF protein and mRNA were present in the cell bodies of a subpopulation of neurons, and BDNF protein was present in the neuropil as punctate or fiber-like structures. In the lateral geniculate nucleus, however, BDNF mRNA was not detected, and BDNF protein was restricted to punctate and fiber-like structures in the neuropil, especially in the most superficial part of the dorsal lateral geniculate nucleus, just below the optic tract. At the ultrastructural level, BDNF protein was localized predominantly to axon terminals containing round synaptic vesicles and pale mitochondria with irregular cristae, which made asymmetric (Gray type I) synaptic specializations (R-boutons). Enucleation of one eye was followed by loss of BDNF immunoreactivity and disappearance of BDNF-positive R-boutons in the contralateral visual centers, confirming the retinal origin of at least most of these terminals. TrkB was present in postsynaptic densities apposed to immunoreactive R-boutons in the superior colliculus and lateral geniculate nucleus, and was also associated with axonal and dendritic microtubules. These findings suggest that BDNF is synthesized by a subpopulation of retinal ganglion cells and axonally transported to visual centers where this neurotrophin is assumed to play important roles in visual system maintenance and/or in modulating the excitatory retinal input to neurons in these centers.

Section snippets

Animals and surgical procedures

Adult male and female Sprague–Dawley rats weighing 200–250 g were used. For surgical procedures the animals were deeply anesthetized with halothane over a mixture of oxygen and nitrous oxide delivered through a nose cone. In four animals the left optic nerve was exposed and transected and the eye removed as described by Campbell and Lieberman (1985). In two other animals the optic nerve was exposed in a sham operation but the nerve and eye left intact. Rats were kept in standard laboratory

Results

The patterns of distribution and intensity of BDNF and TrkB immunoreactivity and of hybridization signals for their mRNAs in the LGN and superior colliculus are illustrated in Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9, Fig. 10, Fig. 11, Fig. 12, Fig. 13, Fig. 14, Fig. 15, Fig. 16, Fig. 17 and summarized in Table 1. Omitting or preabsorbing the primary antibodies eliminated immunoreactivity (e.g. Figs. 7c and 16c). No mRNA signals were detected on sections probed

Discussion

The present study provides new information on the distribution of BDNF and TrkB and the expression patterns of the corresponding mRNAs in the subcortical visual centers of the adult rat, and has described for the first time the ultrastructural localization of the proteins in the LGN and superior colliculus and the changes that occur following elimination of retinal input. The key findings are:

1
BDNF is present in the neuropil of the LGN and superior colliculus, is particularly concentrated in

Acknowledgments

We thank Mark Turmaine for help with the electron microscopy and Fight for Sight for providing the studentship for O.A.

References (74)

T. Abe et al.
Molecular characterization of a novel metabotrophic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction
J Biol Chem
(1992)
T. Amendola et al.
Postnatal changes in nerve growth factor and brain derived neurotrophic factor levels in the retina, visual cortex, and geniculate nucleus in rats with retinitis pigmentosa
Neurosci Lett
(2003)
R. Butowt et al.
Anterograde axonal transport of BDNF and NT-3 by retinal ganglion cellsroles of neurotrophin receptors
Mol Cell Neurosci
(2005)
M. Caleo et al.
Brain-derived neurotrophic factor is an anterograde survival factor in the rat visual system
Curr Biol
(2000)
A. Cellerino et al.
The action of neurotrophins in the development and plasticity of the visual cortex
Prog Neurobiol
(1996)
P. Ernfors et al.
Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family
Neuron
(1990)
G.W. Glazner et al.
Differential effects of BDNF, ADNF9, and TNF alpha on levels of NMDA receptor subunits, calcium homeostasis, and neuronal vulnerability to excitotoxicity
Exp Neurol
(2000)
P.J. Isackson et al.
Comparison of mammalian, chicken and Xenopus brain-derived neurotrophic factor coding sequences
FEBS Lett
(1991)
S. Isenmann et al.
Molecular determinants of retinal ganglion cell development, survival, and regeneration
Prog Ret Eye Res
(2003)
E.S. Levine et al.
Selective role for trkB neurotrophin receptors in rapid modulation of hippocampal synaptic transmission
Brain Res Mol Brain Res
(1996)

A.R. Lieberman et al.

Presynaptic dendrites and a distinctive class of synaptic vesicle in the rat dorsal lateral geniculate nucleus

Brain Res

(1972)

S.Y. Lin et al.

Brain-derived neurotrophic factor enhances association of protein tyrosine phosphatase PTP1D with the NMDA receptor subunit NR2B in the cortical postsynaptic density

Brain Res Mol Brain Res

(1999)

G. Mandolesi et al.

A role for retinal brain-derived neurotrophic factor in ocular dominance plasticity

Curr Biol

(2005)

E. Menna et al.

The anterogradely transported BDNF promotes retinal axon remodeling during eye specific segregation within the LGN

Mol Cell Neurosci

(2003)

J.P. Merlio et al.

Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system

Neuroscience

(1992)

P.T. Ohara et al.

Mode of termination of afferents from the thalamic reticular nucleus in the dorsal lateral geniculate nucleus of the rat

Brain Res

(1980)

M.T. Perez et al.

Expression of brain-derived neurotrophic factor and of its functional receptor in neonatal and adult rat retina

Neurosci Lett

(1995)

B.E. Reese

The projection from the superior colliculus to the dorsal lateral geniculate nucleus in the rat

Brain Res

(1984)

T. Ringstedt et al.

Expression of members of the trk family in the developing postnatal rat brain

Brain Res Dev Brain Res

(1993)

E.M. Schuman

Neurotrophin regulation of synaptic transmission

Curr Opin Neurobiol

(1999)

A.M. Sillito et al.

The contribution of the non-N-methyl-D-aspartate group of excitatory amino acid receptors to retinogeniculate transmission in the cat

Neuroscience

(1990)

K.L. Spalding et al.

Anterograde transport and trophic actions of BDNF and NT-4/5 in the developing rat visual system

Mol Cell Neurosci

(2002)

K. Wu et al.

Brain-derived neurotrophic factor acutely enhances tyrosine phosphorylation of the AMPA receptor subunit GluR1 via NMDA receptor-dependent mechanisms

Brain Res Mol Brain Res

(2004)

Q. Yan et al.

Expression of brain-derived neurotrophic factor (BDNF) protein in the adult rat central nervous system

Neuroscience

(1997)

C. Aoki et al.

Localization of brain-derived neurotrophic factor and TrkB receptors to postsynaptic densities of adult rat cerebral cortex

J Neurosci Res

(2000)

M.M. Bolton et al.

Long-term regulation of excitatory and inhibitory synaptic transmission in hippocampal cultures by brain-derived neurotrophic factor

Prog Brain Res

(2000)

N. Brecha et al.

Substance P-immunoreactive retinal ganglion cells and their central axon terminals in the rabbit

Nature

(1987)

R.J. Cabelli et al.

Changing patterns of expression and subcellular localization of TrkB in the developing visual system

J Neurosci

(1996)

M. Caleo et al.

Provision of brain-derived neurotrophic factor via anterograde transport from the eye preserves the physiological responses of axotomized geniculate neurons

J Neurosci

(2003)

G. Campbell et al.

The olivary pretectal nucleusexperimental anatomical studies in the rat

Philos Trans R Soc Lond B Biol Sci

(1985)

G. Campbell et al.

The localisation of BDNF and TrkB and their mRNAs in the developing and adult rat visual system

Soc Neurosci Abstr

(2001)

A. Cellerino et al.

Brain-derived neurotrophic factor modulates the development of the dopaminergic network in the rodent retina

J Neurosci

(1998)

V. Chaisuksunt et al.

The cell recognition molecule CHL1 is strongly upregulated by injured and regenerating thalamic neurons

J Comp Neurol

(2000)

S. Cohen-Cory et al.

Neurotrophic regulation of retinal ganglion cell synaptic connectivityfrom axons and dendrites to synapses

Int J Dev Biol

(2004)

M. Colonnier et al.

Synaptic organization in the lateral geniculate nucleus of the monkey

Z Zellforsch Mikrosk Anat

(1964)

J.M. Conner et al.

Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNSevidence for anterograde axonal transport

J Neurosci

(1997)

S. Furukawa et al.

Brain-derived neurotrophic factor-like immunoreactivity in the adult rat central nervous system predominantly distributed in neurons with substantial amounts of brain-derived neurotrophic factor messenger RNA or responsiveness to brain-derived neurotrophic factor

Neuroscience

(1998)

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NeuroanatomyPatterns of expression of brain-derived neurotrophic factor and tyrosine kinase B mRNAs and distribution and ultrastructural localization of their proteins in the visual pathway of the adult rat

Abstract

Section snippets

Animals and surgical procedures

Results

Discussion

Acknowledgments

J Biol Chem

Neurosci Lett

Mol Cell Neurosci

Curr Biol

Prog Neurobiol

Neuron

Exp Neurol

FEBS Lett

Prog Ret Eye Res

Brain Res Mol Brain Res

Brain Res

Brain Res Mol Brain Res

Curr Biol

Mol Cell Neurosci

Neuroscience

Brain Res

Neurosci Lett

Brain Res

Brain Res Dev Brain Res

Curr Opin Neurobiol

Neuroscience

Mol Cell Neurosci

Brain Res Mol Brain Res

Neuroscience

Localization of brain-derived neurotrophic factor and TrkB receptors to postsynaptic densities of adult rat cerebral cortex

J Neurosci Res

Long-term regulation of excitatory and inhibitory synaptic transmission in hippocampal cultures by brain-derived neurotrophic factor

Prog Brain Res

Substance P-immunoreactive retinal ganglion cells and their central axon terminals in the rabbit

Nature

Changing patterns of expression and subcellular localization of TrkB in the developing visual system

J Neurosci

Provision of brain-derived neurotrophic factor via anterograde transport from the eye preserves the physiological responses of axotomized geniculate neurons

J Neurosci

The olivary pretectal nucleusexperimental anatomical studies in the rat

Philos Trans R Soc Lond B Biol Sci

The localisation of BDNF and TrkB and their mRNAs in the developing and adult rat visual system

Soc Neurosci Abstr

Brain-derived neurotrophic factor modulates the development of the dopaminergic network in the rodent retina

J Neurosci

The cell recognition molecule CHL1 is strongly upregulated by injured and regenerating thalamic neurons

J Comp Neurol

Neurotrophic regulation of retinal ganglion cell synaptic connectivityfrom axons and dendrites to synapses

Int J Dev Biol

Synaptic organization in the lateral geniculate nucleus of the monkey

Z Zellforsch Mikrosk Anat

Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNSevidence for anterograde axonal transport

J Neurosci

Brain-derived neurotrophic factor-like immunoreactivity in the adult rat central nervous system predominantly distributed in neurons with substantial amounts of brain-derived neurotrophic factor messenger RNA or responsiveness to brain-derived neurotrophic factor

Neuroscience

Neuroanatomy
Patterns of expression of brain-derived neurotrophic factor and tyrosine kinase B mRNAs and distribution and ultrastructural localization of their proteins in the visual pathway of the adult rat