Brain-derived neurotrophic factor regulates the expression of AMPA receptor proteins in neocortical neurons

doi:10.1016/S0306-4522(98)00496-5

Neuroscience

Volume 88, Issue 4, February 1999, Pages 1009-1014

https://doi.org/10.1016/S0306-4522(98)00496-5 Get rights and content

Abstract

The role of the neurotrophins; nerve growth factor,[22]brain-derived neurotrophic factor,[2]neurotrophin-316, 24and neurotrophin-4/5,[3]in synaptic development and plasticity has been extensively investigated.23, 33The neurotrophins regulate synaptic transmission1, 13, 19, 34as well as neural development4, 5, 12, 18, 25in the brain. However, the mechanisms underlying these processes are unknown. In this study we show that brain-derived neurotrophic factor triggers an increase in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor (GluR) proteins without significant changes in their messenger RNA levels. Brain-derived neurotrophic factor treatment specifically increased the protein levels of GluR1 (193±22%) and GluR2/3 (182±11%) in cultured rat neocortical neurons. In contrast, nerve growth factor and neurotrophin-3 failed to alter the protein levels of these neurons, and brain-derived neurotrophic factor effects on N-methyl-D-aspartate-type glutamate receptors were either modest or negligible. Immunocytochemical studies indicated that the increase in AMPA receptor proteins reflects the induction of their neuronal expression, but not selective neuronal survival. In agreement with these results, cortical neurons from brain-derived neurotrophic factor-knockout mice exhibited a reduction in AMPA receptor proteins in the cytoskeletal fraction containing postsynaptic proteins.

Thus, the neurotrophin plays a crucial role in modulating the expression of AMPA receptors presumably at translational or post-translation levels and is implicated in synaptic development and plasticity.

Section snippets

Discussion

In the present study, our results suggest that BDNF can increase specifically protein levels of AMPA receptors. Reversibly, expression of BDNF itself is known to be induced by activation of AMPA receptors in the brain.11, 35Therefore, these two observations indicate that BDNF and AMPA receptors mutually interact with each other to regulate positively the other expression. Their interactions might contribute to normal brain development and plasticity.23, 33

The receptor increase appeared to occur

Acknowledgements

We thank Dr P. Ernfors and Dr R. Jaenisch for providing the brain tissues from BDNF mutant mice, Miss J. H. Kogan and Mrs C. Fujikawa for technical assistance, Dr S. Heinemann for rat GluR1 cDNA, Dr K. Sakimura for mouse GluR2 cDNA and GluR2/3 antibodies, and Dr T. Yamamoto for his advice. This project was supported by the Japan Society for the Promotion of Science (RFTF-96L00203).

References (35)

L.R Berkemeier et al.
Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB
Neuron
(1991)
R.J Cabelli et al.
Blockade of endogenous ligands of trkB inhibits formation of ocular dominance columns
Neuron
(1997)
C.G Causing et al.
Synaptic innervation density is regulated by neuron-derived BDNF
Neuron
(1997)
E.R Chapman et al.
SNAP-25, a t-SNARE which binds to both syntaxin and synaptobrevin via domains that may form coiled coils
J. biol. Chem.
(1994)
A.M Craig et al.
The distribution of glutamate receptors in cultured rat hippocampal neurons: postsynaptic clustering of AMPA-selective subunits
Neuron
(1993)
P Ernfors et al.
Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis
Neuron
(1991)
C Fuhrer et al.
Functional interaction of Src family kinases with the acetylcholine receptor in C2 myotubes
J. biol. Chem.
(1996)
K.R Jones et al.
Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development
Cell
(1994)
M.B Kennedy
The postsynaptic density at glutamatergic synapses
Trends Neurosci.
(1997)
A.K McAllister et al.
Opposing roles for endogenous BDNF and NT-3 in regulating cortical dendritic growth
Neuron
(1997)

R.B McNeill et al.

Interaction of autophosphorylated Ca²⁺/calmodulin-dependent protein kinase II with neuronal cytoskeletal proteins

J. biol. Chem.

(1995)

S.L Patterson et al.

Recombinant BDNF rescues deficits in basal synaptic transmission and hippocamapl LTP in BDNF knockout mice

Neuron

(1996)

S.L Swope et al.

Molecular cloning of two abundant protein tyrosine kinases in Torpedo electric organ that associate with the acetylcholine receptor

J. biol. Chem.

(1993)

Y Akaneya et al.

Brain-derived neurotrophic factor blocks long-term depression in rat visual cortex

J. Neurophysiol.

(1996)

Y.A Barde et al.

Purification of a new neurotrophic factor from mammalian brain

Eur. molec. Biol. Org. J.

(1982)

A Cellerino et al.

The distribution of brain-derived neurotrophic factor and its receptor trkB in parvalbumin-containing neurons of the rat visual cortex

Eur. J. Neurosci.

(1996)

F Conti et al.

Cellular localization and laminar distribution of AMPA glutamate receptor subunits mRNAs and proteins in the rat cerebral cortex

J. comp. Neurol.

(1994)

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Citation Excerpt :
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Letter to NeuroscienceBrain-derived neurotrophic factor regulates the expression of AMPA receptor proteins in neocortical neurons

Abstract

Section snippets

Discussion

Acknowledgements

Neuron

Neuron

Neuron

J. biol. Chem.

Neuron

Neuron

J. biol. Chem.

Cell

Trends Neurosci.

Neuron

J. biol. Chem.

Neuron

J. biol. Chem.

Brain-derived neurotrophic factor blocks long-term depression in rat visual cortex

J. Neurophysiol.

Purification of a new neurotrophic factor from mammalian brain

Eur. molec. Biol. Org. J.

The distribution of brain-derived neurotrophic factor and its receptor trkB in parvalbumin-containing neurons of the rat visual cortex

Eur. J. Neurosci.

Cellular localization and laminar distribution of AMPA glutamate receptor subunits mRNAs and proteins in the rat cerebral cortex

J. comp. Neurol.

Letter to Neuroscience
Brain-derived neurotrophic factor regulates the expression of AMPA receptor proteins in neocortical neurons