The space where aging acts: focus on the <scp>GABA</scp>ergic synapse

Rozycka, Aleksandra; Liguz-Lecznar, Monika

doi:10.1111/acel.12605

Cited by 142 publications

(119 citation statements)

References 154 publications

(189 reference statements)

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“…The altered molecular pathways suggested by these transcriptomic findings include reduced neurotrophic support, neuronal signaling, and GABA function. These pathways have also been implicated in normal lifelong aging of the brain (21,22), lending support to the notion that depression may be associated with accelerated, or anticipated, molecular brain aging (21,23). Finally, functional neuroimaging studies suggest normal aging is associated with blunted CLC processing of emotional faces (24), mirroring neural activity patterns observed in specific depression subtypes (7)(8)(9)(10)12).…”

Section: Introductionmentioning

confidence: 78%

Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms

Marečková

Hawco

Santos

et al. 2019

Preprint

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Background: Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts towards depression-like gene expression patterns. We then mapped this T-PRS onto CLC function and related depressive symptoms in a non-clinical sample of young adults. Methods: Genetic, self-report, and neuroimaging data were available in 482 Duke Neurogenetics Study participants (226 men; age 19.78+/-1.23). T-PRS was generated based on common functional SNPs shifting gene expression in the brain towards a depression-like state. We used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). Posthoc univariate analyses followed up on the link between T-PRS and amygdala reactivity to neutral and threatening faces. For comparison, we generated a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. Results: T-PRS was associated with male-specific reductions in neural response to neutral faces in a widespread network of cortical and subcortical regions (multivariate p=0.03) including the amygdala (beta=-0.14, p=0.04). These results mirrored patterns associated with PGC-PRS independently of sex (ps<0.01). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. Conclusions:We demonstrate for the first time that in men functional SNPs mimicking the postmortem transcriptomic signature of depression are associated with blunted neural activity to social stimuli, which may be expressed as increased anhedonia.

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Section: Introductionmentioning

confidence: 78%

Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms

Marečková

Hawco

Santos

et al. 2019

Preprint

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“…An age‐related reduction in GABAergic input might contribute to attenuated photic entrainment (Benloucif, Masana, & Dubocovich, ; Zhang et al., ) and altered coordination of circadian oscillators during senescence (Davidson, Yamazaki, Arble, Menaker, & Block, ; Yamazaki et al., ). As well as the SCN, age‐related impairments in GABAergic systems have been identified in the cortex and other brain regions and have been implicated in cognitive impairments associated with aging and neurodegeneration (see Rozycka & Liguz‐Lecznar, for review).…”

Section: Neural Mechanisms Regulating Circadian Rhythms and How They mentioning

confidence: 99%

Interacting influences of aging and Alzheimer's disease on circadian rhythms

Duncan

2019

Eur J of Neuroscience

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Aging leads to changes in circadian rhythms, including decreased amplitude or robustness, altered synchrony with the environment, and reduced coordination of rhythms within body. These circadian rhythm alterations are more pronounced in age‐associated neurodegenerative disorders such as Alzheimer's disease (AD), in which they often precede the onset of other symptoms by many years. As well as their early onset, the findings that fragmentation of daily rest‐activity rhythms in non‐demented older subjects is associated earlier cognitive decline, increased risk of incident AD, and preclinical AD neuropathology, suggest that circadian rhythm disruption may contribute to the development and progression of the neuropathological changes occurring in AD. Conversely, other studies have implicated amyloid‐beta, a prominent neurotoxin that accumulates in AD, in the impairment of circadian rhythms. Thus, circadian rhythm disruption and AD‐associated neurodegeneration may interact to form a deleterious cycle. This article reviews the neural and molecular mechanisms underlying the age‐ and AD‐related changes in circadian rhythms. It also explores therapeutic strategies proposed to ameliorate circadian rhythm deficits in elderly and demented individuals.

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“…Vulnerability of inhibitory cortical interneurons towards aging 674Besides reduced excitability and plasticity(Clark & Taylor, 2011) and a decline of inhibitory 675 function(Cheng & Lin, 2013;Shetty & Turner, 1998;Stanley & Shetty, 2004), selective 676 vulnerability of particular neuronal subtypes, like inhibitory interneurons, and GABAergic synapses 677(Rozycka & Liguz-Lecznar, 2017) was reported for brain aging. Indeed, given the crucial role 678 GABAergic inhibitory interneurons have in cortical information processing, age-dependent defects in 679 inhibitory circuits provide an attractive hypothesis for the cognitive decline and age-associated 680 disorders(Rozycka & Liguz-Lecznar, 2017). 681In agreement with our finding that PV interneuron numbers were reduced in old cortices, several 682 studies reported declined cell numbers of cortical interneuron subtypes across different species and 683 brain regions (reviewed inZimmer-Bensch, 2019).…”

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confidence: 99%

DNA methyltransferase 1 (DNMT1) function is implicated in the age-related loss of cortical interneurons

Hahn

Bayer

Pensold

et al. 2020

Preprint

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36Increased life expectancy in modern society comes at the cost of age-associated disabilities and 37 diseases. Aged brains not only show reduced excitability and plasticity, but also a decline in 38 inhibition. Age-associated defects in inhibitory circuits likely contribute to cognitive decline and age-39 related disorders. Molecular mechanisms that exert epigenetic control of gene expression, contribute 40 Running Title 2 This is a provisional file, not the final typeset article to age-associated neuronal impairments. Both DNA methylation, mediated by DNA 41 methyltransferases (DNMTs), and histone modifications maintain neuronal function throughout 42 lifespan. Here we provide evidence that DNMT1 function is implicated in the age-related loss of 43 cortical inhibitory interneurons. Deletion of Dnmt1 in parvalbumin-positive interneurons attenuates 44 their age-related decline in the cerebral cortex. Moreover, DNMT1-deficient mice show improved 45 somatomotor performance and reduced aging-associated transcriptional changes. A decline in the 46 proteostasis network, responsible for the proper degradation and removal of defective proteins, is 47 suggested to be essentially implicated in age-and disease-related neurodegeneration. Our data 48 suggest that DNMT1 acts indirectly on interneuron survival in aged mice by modulating the 49 proteostasis network during life-time. 50 51

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The space where aging acts: focus on the GABAergic synapse

Cited by 142 publications

References 154 publications

Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms

Novel polygenic risk score as a translational tool linking depression-related changes in the corticolimbic transcriptome with neural face processing and anhedonic symptoms

Interacting influences of aging and Alzheimer's disease on circadian rhythms

DNA methyltransferase 1 (DNMT1) function is implicated in the age-related loss of cortical interneurons

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