Mice Heterozygous for Neurotrophin-3 Display Enhanced Vulnerability to Excitotoxicity in the Striatum Through Increased Expression of N-methyl-d-aspartate Receptors.
From: Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain.
Neuroscience
- Publish Date: Jan 2007
- ISSN: 0306-4522
- Volume: 144
- Issue: 2
- Pages: 462-71
- Medium: Print
- Language: English
- Citation (JAMA): Torres-Peraza J, Pezzi S, Canals J M, et al. Mice Heterozygous for Neurotrophin-3 Display Enhanced Vulnerability to Excitotoxicity in the Striatum Through Increased Expression of N-methyl-d-aspartate Receptors.. Neuroscience Jan 2007;144:462-71
Abstract
The striatum is one of the brain areas most vulnerable to excitotoxicity, a lesion that can be prevented by neurotrophins. In the present study, intrastriatal injection of the N-methyl-d-aspartate receptor (NMDAR) agonist quinolinate (QUIN) was performed in mice heterozygous for neurotrophin-3 (NT3 +/-) or brain-derived neurotrophic factor (BDNF +/-) to analyze the role of endogenous neurotrophins on the regulation of striatal neurons susceptibility to excitotoxic injury. QUIN injection induced a decrease in dopamine- and cyclic AMP-regulated phosphoprotein of 32 kDa (DARPP-32) protein levels that was higher in NT-3 +/- than in BDNF+/- or wild type animals. This enhanced susceptibility was specific for enkephalin- and tachykinin-positive projection neurons, and also for parvalbumin-positive interneurons. However the excitotoxic damage in large interneurons was not modified in NT-3 +/- mice compared with wild type animals. This effect can be related to the regulation of NMDARs by endogenous NT-3. Thus, our results show that there is an age-dependent regulation of NMDAR subunits NR1 and NR2A, but not NR2B, in NT-3 +/- mice. The deficit of endogenous NT-3 induced a decrease in NR1 and NR2A subunits at postnatal day (P) 0 and P3 mice respectively, whereas an upregulation was observed in 12 week old NT-3 +/- mice. This differential effect was also observed after administration of exogenous NT-3. In primary striatal cultures, NT-3 treatment induced an enhancement in NR2A, but not NR2B, protein levels. However, intrastriatal grafting of NT-3 secreting-cells in adult wild type mice produced a down-regulation of NR2A subunit. In conclusion, NT-3 regulates the expression of NMDAR subunits modifying striatal neuronal properties that confers the differential vulnerability to excitotoxicity in projection neurons and interneurons in the striatum.
Mesh Headings (Keywords): Analysis of Variance, Animals, Brain-Derived Neurotrophic Factor, Cell Count, Cell Transplantation, Cells, Cultured, Corpus Striatum, Excitatory Amino Acids, Fibroblasts, Gene Expression Regulation, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Neurotrophin 3, Quinolinic Acid, Rats, Rats, Inbred F344, Receptors, N-Methyl-D-Aspartate, Transfection, Transplantation, Heterologous, gamma-Aminobutyric Acid
Check for Full Text / PubMed Unique Identifier (PMID): 17081696
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