Intrastriatal infusion of nerve growth factor after quinolinic acid prevents reduction of cellular expression of choline acetyltransferase messenger RNA and trkA messenger RNA, but not glutamate decarboxylase messenger RNA.
Excitotoxic striatal lesions induced by quinolinic acid, a model for Huntington's disease, were used to test for neuroprotective actions of nerve growth factor on striatal cholinergic and GABAergic neurons. Expressions of the trkA receptor for nerve growth factor, choline acetyltransferase and glutamate decarboxylase were analysed by messenger RNA in situ hybridization in adult rats following quinolinic acid lesion (150 nmol) and daily striatal administration of nerve growth factor (1 microgram) or control protein (cytochrome C) for one week. One week after toxin administration, the numbers of cells expressing trkA or choline acetyltransferase messenger RNAs were decreased when compared with unlesioned animals. Moreover, the surviving cells showed a strong down-regulation of these messenger RNAs as deduced from grain count analysis of sections processed for emulsion autoradiography. Daily intrastriatal nerve growth factor administration for one week completely prevented the reduction in the number of cells expressing either of the two markers. Nerve growth factor treatment increased the cellular expression of choline acetyltransferase messenger RNA three times above control levels and restored the levels of trk A messenger RNA expression to control levels. In contrast to the protective effects on cholinergic cells, nerve growth factor treatment failed to attenuate the quinolinic acid-induced decrease in glutamate decarboxylase messenger RNA levels. Optical density measurements of the entire striatum on autoradiographs of brain sections from quinolinic acid-lesioned animals revealed a reduction of the glutamate decarboxylase messenger RNA-specific hybridization signal, which was unaltered by infusion of nerve growth factor or control protein. Our findings strongly suggest that in both the intact and the quinolinic acid-lesioned adult rat striatum, nerve growth factor action is confined to trk A-expressing cholinergic neurons. Striatal glutamate decarboxylase messenger RNA-expressing GABAergic neurons which degenerate in Huntington's disease are not responsive to nerve growth factor.
Division of Neurogerontology, Andrus Gerontology Center, University of Southern California, Los Angeles 90089.
J L
JL
Venero
K D
KD
Beck
F
F
Hefti
D000818:Animals; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis* / Q000235:genetics; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D006816:Huntington Disease; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D017378:Quinolinic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000235:genetics
D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D005968:Glutamate Decarboxylase; D017378:Quinolinic Acid