Effects of aging on quinolinic acid lesions in rat striatum

Finn, Stephen F.; Hyman, Bradley T.; Storey, Elsdon; Miller, Julie; Beal, M. Flint

doi:10.1016/0006-8993(91)90631-5

Cited by 19 publications

(10 citation statements)

References 35 publications

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“…Contrary to the pre-symptomatic assay and consistent with previous studies in rats and FVB mice [76,155,156], both D9-N171-98Q and nontransgenic C57BL/6J mice show a dramatic age-dependent decrease in sensitivity to QA, exhibiting a 10-fold and 2-fold decrease in FJ-positive neurons, respectively, compared to their younger counterparts. Symptomatic D9-N171-98Q mice showed greater resistance to excitotoxicity relative to pre-symptomatic D9-N171-98Q mice (p00.0001) and also relative to age-matched nontransgenic mice (p00.027), similar to data from pan-cellular HD models [76,149,157].…”

Section: Excitotoxicitysupporting

confidence: 88%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

121

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Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

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Section: Excitotoxicitysupporting

confidence: 88%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

121

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“…Widespread evidence was found here of decreased mitochondrial function (Table 1A, on-line Table 3). In addition, genes for GluR5-2 and KAT, which both favor synaptic inhibition (Vignes et al, 1998;Moroni, 1999), were upregulated ACRGs (Table 4), and the product of KAT, kynurenic acid, increases with aging (Finn et al, 1991;Moroni, 1999). Electrophysiological data also support the conclusion that glutamatergic and adrenergic transmission are decreased with aging (Barnes, 1994;Bickford et al, 2000).…”

Section: Neuronal Triggers Of Demyelinationmentioning

confidence: 61%

Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

et al. 2003

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Gene expression microarrays provide a powerful new tool for studying complex processes such as brain aging. However, inferences from microarray data are often hindered by multiple comparisons, small sample sizes, and uncertain relationships to functional endpoints. Here we sought gene expression correlates of aging-dependent cognitive decline, using statistical profiling of gene microarrays in well powered groups of young, mid-aged, and aged rats (n ϭ 10 per group). Animals were trained on two memory tasks, and the hippocampal CA1 region of each was analyzed on an individual microarray (one chip per animal). Aging-and cognition-related genes were identified by testing each gene by ANOVA (for aging effects) and then by Pearson's test (correlating expression with memory). Genes identified by this algorithm were associated with several phenomena known to be aging-dependent, including inflammation, oxidative stress, altered protein processing, and decreased mitochondrial function, but also with multiple processes not previously linked to functional brain aging. These novel processes included downregulated early response signaling, biosynthesis and activity-regulated synaptogenesis, and upregulated myelin turnover, cholesterol synthesis, lipid and monoamine metabolism, iron utilization, structural reorganization, and intracellular Ca 2ϩ release pathways. Multiple transcriptional regulators and cytokines also were identified. Although most gene expression changes began by mid-life, cognition was not clearly impaired until late life. Collectively, these results suggest a new integrative model of brain aging in which genomic alterations in early adulthood initiate interacting cascades of decreased signaling and synaptic plasticity in neurons, extracellular changes, and increased myelin turnover-fueled inflammation in glia that cumulatively induce agingrelated cognitive impairment.

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“…H: Magnification of the area indicated by arrows in G. As with young rats (C and 0), no damage was induced by PDC in any of the five aged animals perfused with this drug. Bar = 100 jim in A, C, E, and G and 25 jim in B, D, F, and H. effects of quinolinic (Finn et al, 1991) and kainic (Kesslak et al, 1995) acids. Our finding that the damage produced by DHK in the striatum was diminished significantly in the aged group is in agreement with this interpretation.…”

Section: Discussionmentioning

confidence: 99%

“…It is interesting that both types of lesions apparently lead to secondary excitotoxic mechanisms Schulz et a!., 1994). An increased vulnerability of aged individuals to the neurological or epileptogenic effects of domoic acid in humans and of kainic acid in rats has also been described (Teitelbaum et al, 1990;Wozniak et a!., 1991), although other reports show that aged rats are less susceptible to the excitotoxic action of kainic and quinolinic acids (Finn et al, 1991;Kesslak et a!., 1995).…”

mentioning

confidence: 98%

Glutamate Uptake Impairment and Neuronal Damage in Young and Aged Rats In Vivo

Massieu

Tapia

1997

Journal of Neurochemistry

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Abstract:The extracellular concentration of glutamate increases during hypoxia/ischemia probably due to deficient uptake. Glutamate might contribute to neuronal damage associated with this disorder and to neurodegeneration during aging. In the present study, we have tested the effect of two inhibitors of glutamate transport, L-transpyrrolidine-2,4-dicarboxylate and dihydrokainate, on the extracellularlevels of glutamate and on neuronal damage, which was quantitatively studied by image analysis of histological brain sections. Drugs were administered by microdialysis and glutamate concentration was determined by HPLC in the striatum and the hippocampus of 3-month-old and 22-24-month-old rats. In both regions studied, the basal concentration of extracellular glutamate was higher in aged than in young rats. Pyrrolidine dicarboxylate induced a substantial elevation of extracellular glutamate in both regions, and although this increase was almost twofold higher in old than in young animals, no neuronal damage was observed. In contrast, dihydrokainate had a poor effect on glutamate levels, but induced clear neuronal damage in the striatum and the hippocampus in both groups of rats. The present results suggest that age appears not to be a significant factor in the sensitivity of neurons to the toxic effect of extracellular glutamate increase via blockade of its transport system. Key Words: Dihydrokainate-Glutamate uptake-Hippocampus-Microdialysis-Neuronal damage-Pyrrolidine dicarboxylate-Striatum.

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Effects of aging on quinolinic acid lesions in rat striatum

Cited by 19 publications

References 35 publications

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

Glutamate Uptake Impairment and Neuronal Damage in Young and Aged Rats In Vivo

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