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Glutamate stimulates neurotrophin expression in cultured Müller cells

Posted by on in 2003
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 Sara Taylor, Bhooma Srinivasan, Robert J. Wordinger and Rouel S. Roque,
Molecular Brain Research, Volume 111, Issues 1-2 , 17 March 2003, Pages 189-197
Department of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Accepted 7 January 2003; Available online 31 January 2003.

Abstract

The uptake of excess extracellular glutamate and the secretion of neurotrophins by glial cells have been suggested to protect CNS neurons from glutamate-induced toxicity. In the retina, perturbation of glutamate transport and decreased retrograde transport of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) may contribute to ganglion cell death in experimental glaucoma. Although many studies show a clear relationship between glutamate and neurotrophic factors, such relationship has not been thoroughly investigated in the retinal environment. In the following study, we determined the effects of glutamate on early passaged rat Müller cells, specifically their expression of neurotrophic factors including BDNF, nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and glial-cell line derived neurotrophic factor (GDNF); and of glutamate receptors and transporters using immunoblots or enzyme-linked immunosorbent assays. Binding of BDNF to its cognate receptor TrkB was also determined using co-immunoprecipitation studies. Cultured Müller cells grown in the presence of glutamate were also assayed for survival using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). Our study showed that while glutamate treatment did not promote cell death, it upregulated secretion of BDNF, NGF, NT-3, NT-4, and GDNF by Müller cells. While solitary bands at ~13-14 kDa were observed for NGF, NT-3, and NT-4; two BDNF-reactive bands were observed in immunoblots: a faster migrating band at the reported size of the BDNF monomer (~13 kDa); and a more intense band at ~36 kDa. GDNF-reactive bands were observed at ~22, ~28, and ~55 kDa. Glutamate also induced significant changes in glutamate receptor and transporter proteins, as well maintained the association of BDNF to TrkB in Müller cells. The decreased N-methyl--aspartate receptor (NMDAR) levels and sustained activation of TrkB by BDNF could serve as protective mechanisms for Müller cell survival. Moreover, the increased secretion of neurotrophic factors and upregulation of -glutamate/-aspartate transporter (GLAST) expression in Müller cells may protect retinal neurons from glutamate toxicity.

Author Keywords: Brain-derived neurotrophic factor; Excitatory amino acid transporters; Glutamate transporter 1; -Glutamate/-aspartate transporter; Glial-cell line derived neurotrophic factor; Müller cells; Nerve growth factor; Neurotrophin-3; Neurotrophin-4; N-Methyl--aspartate receptor; trkB

Neuroscience classification codes: Neurotransmitters, modulators, transporters, and receptors, Excitatory amino acids: excitotoxicity

Corresponding author. Department of Pathology and Anatomy, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2699, USA. Tel.: +1-817-735-5055; fax: +1-817-735-2610.

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