Age-correlated decline in [3H]tiagabine binding to GAT-1 in human frontal cortex

Sundman-Eriksson, Ingrid; Allard, Per

doi:10.1007/bf03324657

Cited by 11 publications

(8 citation statements)

References 23 publications

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“…Older patients seem to express less SLC6A1 than younger patients, although this will require confirmation on a protein level. This finding is consistent with a recent postmortem study showing that aging is associated with a loss of [ 3 H]-tiagabine binding in frontal cortex [33]. Lower levels of SLC6A1 in older patients may imply that lower dosages of drugs such as tiagabine are required to block a certain fraction of transporters.…”

Section: Discussionsupporting

confidence: 92%

Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity

Hirunsatit

George²,

Lipska

et al. 2009

Pharmacogenetics and Genomics

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Objective-Sodium-dependent and chloride-dependent γ-aminobutyric acid (GABA) transporter 1 (SLC6A1) is the target of a number of drugs of clinical importance and is a major determinant of synaptic GABA concentrations. We resequenced the human SLC6A1 gene previously and discovered a novel 21 bp insertion in the predicted promoter region that creates a second tandem copy of the sequence. Here we sought to determine the functional relevance of this variation.Methods-We used reporter assays, mobility shift assays, quantitative PCR, and proteomics methods as well as postmortem expression analysis for this work.Results-Reporter assays showed that the insertion allele significantly increases promoter activity in multiple cell lines. The zinc finger transcription factor ZNF148 was found to significantly transactivate the promoter and increase expression when overexpressed but could not account for the differences in activity between the two alleles of the promoter. Copy number of the insertion Conflicts of interest: Dr Gelernter has received financial support or compensation from the following: related to consultation for Columbia University, the University of CT Health Center, NIH, and Faegre & Benson; related to grant reviews for the National Institutes of Health; and related to academic lectures and editorial functions in various scientific venues (including for the ACNP). Dr Lappalainen is currently employed by AstraZeneca Pharmaceuticals. His effort on this project was restricted to the time that he was employed by Yale University and the West Haven VA Healthcare System. NIH Public AccessAuthor Manuscript Pharmacogenet Genomics. Author manuscript; available in PMC 2009 December 10. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sequence was associated with exponentially increasing activity of a downstream promoter, suggesting that the insertion sequence has enhancer activity when present in multiple copies. SLC6A1 promoter genotype was found to predict SLC6A1 RNA expression in human postmortem hippocampal samples. These results suggest that the insertion polymorphism leads to increased SLC6A1 promoter activity because, in part, of creation of an enhancer element when present as multiple copies. Genotyping individuals from Tanzania in this study suggested that the insertion allele has its origin in Africa.Conclusion-On account of the effect of the insertion on promoter activity, this relatively common polymorphism may prove useful in predicting clinical response to pharmacological modulators of SLC6A1 as well as GABAergic function in individuals of African descent.

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Section: Discussionsupporting

confidence: 92%

Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity

Hirunsatit

George²,

Lipska

et al. 2009

Pharmacogenetics and Genomics

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“…However, it has previously been hypothesized that slower dynamics for older people is caused by increased inhibitory activity in visual cortex 39 , but no arguments were provided to exclude the role of adaptation and/or noise. There are observations using post-mortem brains of an age-related decline in gamma-aminobutyric acid (GABA) transporters in human cortex 48 . However, this was only found in frontal cortex and it is known that GABA transporter densities are highly variable in human cortex 49 .…”

Section: Discussionmentioning

confidence: 99%

Changes in low-level neural properties underlie age-dependent visual decision making

Wezel

2018

Sci Rep

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Aging typically slows down cognitive processes, specifically those related to perceptual decisions. However, the neurobiological mechanisms underlying these age-associated changes are still elusive. To address this, we studied the effect of aging on both perceptual and binocular rivalry in various presentation conditions. Two age groups of participants reported their spontaneous percept switches during continuous presentation and percept choices during intermittent presentation. We find no significant age effect on the mean and cumulative frequencies of percept switch durations under continuous presentation. However, the data show a significant age effect on coefficient of variation, ratio of standard deviation to mean of percept durations. Our results also reveal that the alternation rate for percept choices significantly declines at an older age under intermittent presentation. The latter effect is even more pronounced at shorter inter-stimulus durations. These results together with the predictions of existing neural models for bistable perception imply that age-dependency of visual perceptual decisions is caused by shifts in neural adaptation and noise, not by a change in inhibition strength. Thus, variation in the low-level neural properties, adaptation and noise, cause age-dependent properties in visual perceptual decisions.

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“…Why GABA is reduced after noise exposure, yet not with aging is still unclear and the physiological consequences of reduced PV and MBP expression also remain to be clarified. However, in human populations, it is known that cortical inhibitory transmitters can change in complex ways throughout the lifespan (Sundman-Eriksson and Allard, 2006; Pinto et al, 2010), potentially contributing to changes in sensory processing in old age. Thus, they represent an exciting target for research on aging, and experiments are currently underway in our laboratory to explore this area.…”

Section: Discussionmentioning

confidence: 99%

Shaping the aging brain: role of auditory input patterns in the emergence of auditory cortical impairments

Kamal¹,

Holman²,

Villers-Sidani³

2013

Front. Syst. Neurosci.

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Age-related impairments in the primary auditory cortex (A1) include poor tuning selectivity, neural desynchronization, and degraded responses to low-probability sounds. These changes have been largely attributed to reduced inhibition in the aged brain, and are thought to contribute to substantial hearing impairment in both humans and animals. Since many of these changes can be partially reversed with auditory training, it has been speculated that they might not be purely degenerative, but might rather represent negative plastic adjustments to noisy or distorted auditory signals reaching the brain. To test this hypothesis, we examined the impact of exposing young adult rats to 8 weeks of low-grade broadband noise on several aspects of A1 function and structure. We then characterized the same A1 elements in aging rats for comparison. We found that the impact of noise exposure on A1 tuning selectivity, temporal processing of auditory signal and responses to oddball tones was almost indistinguishable from the effect of natural aging. Moreover, noise exposure resulted in a reduction in the population of parvalbumin inhibitory interneurons and cortical myelin as previously documented in the aged group. Most of these changes reversed after returning the rats to a quiet environment. These results support the hypothesis that age-related changes in A1 have a strong activity-dependent component and indicate that the presence or absence of clear auditory input patterns might be a key factor in sustaining adult A1 function.

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Age-correlated decline in [3H]tiagabine binding to GAT-1 in human frontal cortex

Cited by 11 publications

References 23 publications

Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity

Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity

Changes in low-level neural properties underlie age-dependent visual decision making

Shaping the aging brain: role of auditory input patterns in the emergence of auditory cortical impairments

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