N-methyl- d-aspartate receptor activation in the neostriatum increases c-fos and fos-related antigens selectively in medium-sized neurons

Abstract

In the neostriatum a selective loss of neurons occurs following exposure toN-methyl- d-aspartate receptor agonists. One hypothesis emerging from this observation is that an excitotoxic process viaN-methyl- d-aspartate receptors may contribute to the pathogenesis of Huntington's disease, which is characterized by the loss of medium-sized neurons. However, whether there is a selective distribution ofN-methyl- d-aspartatereceptors in specific populations of neostriatal neurons is unknown. In this study the expression of c-fos mRNA and protein was used to examine the response of neostriatal cells toN-methyl- d-aspartatereceptor stimulation in the rat. After intrastriatal injection of theN-methyl- d-aspartate receptor agonist, quinolinic acid, an increase in c-fos mRNA concentrations was detected using in situ hybridization and Northern blot analysis. Western blot analysis showed that not only the c-Fos mRNA protein product but also other Fos-related antigens capable of binding to DNA were increased in response toN-methyl- d-aspartate receptor activation. The selectivity of the neuronal response toN-methyl- d-aspartate receptor activation was examined immunohistochemically at the light and ultra structural levels. Our results indicate thatN-methyl- d-aspartate receptor activation by quinolinic acid stimulates medium spiny neurons to increase c-Fos expression; to a lesser extent, medium aspiny interneurons and glial cells also respond. In contrast, negligible change in c-Fos expression is observed in large neurons. These results are consistent with other evidence that medium-sized spiny neurons are preferentially vulnerable to the toxic effects of excitatory amino acids acting atN-methyl- d-aspartate receptors. An additional implication of these findings is that activation of theN-methyl- d-aspartatereceptor in medium spiny neurons leads to increased expression of candidate AP-1 transcription factors, thereby coupling theN-methyl- d-aspartate receptor and regulation of gene expression in signal transduction processes of the neostriatal medium spiny neuron.