Mice heterozygous for neurotrophin-3 display enhanced vulnerability to excitotoxicity in the striatum through increased expression of N-methyl-D-aspartate receptors.
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.
Torres-Peraza
J
J
Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain.
Pezzi
S
S
Canals
J M
JM
Gavaldà
N
N
García-Martínez
J M
JM
Pérez-Navarro
E
E
Alberch
J
J
D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency; D002452:Cell Count / Q000379:methods; D017690:Cell Transplantation; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D018846:Excitatory Amino Acids / Q000633:toxicity; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020933:Neurotrophin 3 / Q000172:deficiency / Q000502:physiology*; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014183:Transplantation, Heterologous; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D018846:Excitatory Amino Acids; D020933:Neurotrophin 3; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D017378:Quinolinic Acid