ABSTRACT
Striatal neurons in symptomatic Huntington's disease (HD) transgenic mice are resistant to a variety of toxic insults, including quinolinic acid (QA), kainic acid and 3-nitropropionic acid. The basis for this resistance is currently unknown. To investigate the possibility that the immediate-early gene (IEG) response is defective in symptomatic HD mice leading to a lack of response to these compounds, we examined the expression of c-Fos and Krox 24 after administration of the indirect dopamine agonist methamphetamine, the dopamine D(2) receptor antagonist haloperidol and the neurotoxin QA in 5- and 10-week-old R6/2 transgenic HD and wild-type mice. Unlike wild-type and pre-symptomatic R6/2 transgenic HD mice, 10-week-old symptomatic HD mice were resistant to methamphetamine-induced gliosis and QA lesion. There was, however, no difference in the number or distribution of c-Fos-immunoreactive nuclei 2 hr after single injections of methamphetamine or haloperidol among 5- and 10-week-old wild-type mice and 5- and 10-week-old R6/2 HD mice. Similarly, despite their resistance to QA-induced lesioning and lower basal levels of krox-24 mRNA, the symptomatic R6/2 mice had equivalent increases in the amount of c-fos and krox-24 mRNA compared to wild-type and pre-symptomatic R6/2 HD mice as determined by in situ hybridization and densitometry 2 hr after QA administration. These data demonstrate that the c-Fos and Krox 24 IEG response to dopamine agonists, dopamine antagonists and neurotoxic insult is functional in symptomatic R6/2 HD mice. Resistance to toxic insult in R6/2 mice may be conferred by interactions of mutant huntingtin with proteins or transcriptional processes further along the toxic cascade.
Subject(s)
Genes, Immediate-Early/drug effects , Haloperidol/pharmacology , Huntington Disease/metabolism , Immediate-Early Proteins , Methamphetamine/pharmacology , Nerve Tissue Proteins , Quinolinic Acid/pharmacology , Animals , Anti-Dyskinesia Agents/pharmacology , Central Nervous System Stimulants/pharmacology , Corpus Callosum/drug effects , Corpus Callosum/metabolism , Corpus Callosum/pathology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/pathology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Disease Models, Animal , Dopamine Antagonists/pharmacology , Dopamine and cAMP-Regulated Phosphoprotein 32 , Early Growth Response Protein 1 , Gene Expression/drug effects , Glial Fibrillary Acidic Protein/metabolism , Huntington Disease/genetics , Huntington Disease/pathology , Mice , Mice, Transgenic , Phosphoproteins/metabolism , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
OBJECTIVE: We investigated event-related brain potentials (ERPs) elicited by a novel speech comprehension paradigm modelled after the neuropsychological Token Test. The objective of the study was to determine whether the ERPs were sensitive to differences in the initial phonemes of the speech stimuli. METHODS: Twenty-seven healthy subjects identified incorrect spoken sentences on the computerised Token Test (CTT). The incorrect spoken sentences contained one word that did not match the previously studied animations. The initial phonemes of these words were either different than or similar to the initial phonemes of their correct counterparts. RESULTS: Different initial phonemes were associated with an early N2b, while words having similar initial phonemes resulted in a substantially delayed N2b. CONCLUSION: The delayed latency effect was due to whether the incorrect word's initial phoneme matched or mismatched that of the expected word. In both cases, this component reflected a mismatch with an existing cognitive template maintained in phonological working memory. The results indicate that this mismatching effect reflected primarily attentional detection rather than language processing.
