Glial Dysfunction Causes Age-Related Memory Impairment in Drosophila

Yamazaki, Daisuke; Horiuchi, Junjiro; Ueno, Kohei; Ueno, Taro; Saeki, Shinjiro; Matsuno, Motomi; Naganos, Shintaro; Miyashita, Tomoyuki; Hirano, Yukinori; Nishikawa, Hiroyuki; Taoka, Masato; Yamauchi, Yoshio; Isobe, Toshiaki; Honda, Yoshiaki; Kodama, Tohru; Masuda, Tomoko; Saitoe, Minoru

doi:10.1016/j.neuron.2014.09.039

Cited by 53 publications

(63 citation statements)

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“…Our analyses indicate that there are 49 genes with astrocyte-enriched expression encoding membrane transporters or ion channels, including Irk channels, the GABA transporter, an SLC5A transporter (CG9657) and GABA Transaminase ( GABAT ), a mitochondrial protein known to be expressed in glial cells and important for sleep regulation (Chen et al, 2015). Enriched or high-level expression was observed for other known fly glial genes in our analysis (Table S5): these encode Glutamine synthase 2, Glutamate oxaloacetate transaminase isoforms ( Got 1 and Got2 ), Dopamine acetyltransferase and Pyruvate decarboxylase (recently implicated in age-dependent memory impairment, Yamazaki et al, 2014). The glutamate transporter ( eaat1 ) gene is expressed in fly astrocytes (~800 reads) but was not enriched relative to total RNA in our analysis (~1300 reads).…”

Section: Resultsmentioning

confidence: 75%

“…Drosophila glia-neuron interactions are known to be important for development of the fly nervous system as well as normal and pathological neuronal degeneration that occurs in the adult brain (Doherty et al, 2009; Miller et al, 2012; Petersen et al, 2012; Hakim et al, 2014; Tasdemir-Yilmaz and Freeman, 2014), but only recently has it been documented that such interactions are important for adult behavior. Recent studies, for example, show that glia-neuron signaling in the Drosophila brain is an important component of circuit interactions that control neuronal excitability (Melom and Littleton, 2013; Rusan et al, 2014), circadian behavior (Ng et al, 2011; Jackson et al, 2015), sleep (Seugnet et al, 2011; Chen et al, 2015), olfaction (Liu et al, 2014), vision (Borycz et al, 2012; Rahman et al, 2012; Xu et al, 2015) and memory formation (Yamazaki et al, 2014; Matsuno et al, 2015). Given these findings, it is of interest to define glial factors, including secreted proteins, which mediate communication with neurons.…”

Section: Introductionmentioning

confidence: 99%

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TRAP-seq Profiling and RNAi-Based Genetic Screens Identify Conserved Glial Genes Required for Adult Drosophila Behavior

Sengupta

Huang

et al. 2016

Front. Mol. Neurosci.

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Although, glial cells have well characterized functions in the developing and mature brain, it is only in the past decade that roles for these cells in behavior and plasticity have been delineated. Glial astrocytes and glia-neuron signaling, for example, are now known to have important modulatory functions in sleep, circadian behavior, memory and plasticity. To better understand mechanisms of glia-neuron signaling in the context of behavior, we have conducted cell-specific, genome-wide expression profiling of adult Drosophila astrocyte-like brain cells and performed RNA interference (RNAi)-based genetic screens to identify glial factors that regulate behavior. Importantly, our studies demonstrate that adult fly astrocyte-like cells and mouse astrocytes have similar molecular signatures; in contrast, fly astrocytes and surface glia—different classes of glial cells—have distinct expression profiles. Glial-specific expression of 653 RNAi constructs targeting 318 genes identified multiple factors associated with altered locomotor activity, circadian rhythmicity and/or responses to mechanical stress (bang sensitivity). Of interest, 1 of the relevant genes encodes a vesicle recycling factor, 4 encode secreted proteins and 3 encode membrane transporters. These results strongly support the idea that glia-neuron communication is vital for adult behavior.

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Section: Resultsmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

TRAP-seq Profiling and RNAi-Based Genetic Screens Identify Conserved Glial Genes Required for Adult Drosophila Behavior

Sengupta

Huang

et al. 2016

Front. Mol. Neurosci.

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“…Since the neuronal circuits of the mushroom bodies and central complex are known to regulate behaviors that are affected by aging, such as learning and memory, locomotor activity and walking (Martin et al, 1998, 1999; Grotewiel et al, 2005; Yamazaki et al, 2014; Ismail et al, 2015), we used antibody markers to study effects of dormancy and aging on these brain centers.…”

Section: Resultsmentioning

confidence: 99%

“…Only more subtle signs of aging have been revealed in the fly: central neurons do display some ultrastructural changes (Martín-Peña et al, 2006) and certain structural and molecular features were shown to be affected in axon terminations of motor neurons (Beramendi et al, 2007; Wagner et al, 2015). On the other hand, many behaviors, including learning and memory, are known to deteriorate over the lifespan (Grotewiel et al, 2005; Tonoki and Davis, 2012; Yamazaki et al, 2014) suggesting that aging induces deleterious effects on neurons and neuronal circuits in the Drosophila brain. One aim of this study is to reveal such aging-induced changes in brain neurons and try to relate them to behavioral senescence.…”

Section: Introductionmentioning

confidence: 99%

Behavioral Senescence and Aging-Related Changes in Motor Neurons and Brain Neuromodulator Levels Are Ameliorated by Lifespan-Extending Reproductive Dormancy in Drosophila

Liao

Broughton

Nässel

2017

Front. Cell. Neurosci.

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The lifespan of Drosophila melanogaster can be extended substantially by inducing reproductive dormancy (also known as diapause) by lowered temperature and short days. This increase of longevity is accompanied by lowered metabolism and increased stress tolerance. We ask here whether behavioral senescence is ameliorated during adult dormancy. To study this we kept flies for seven or more weeks in normal rearing conditions or in diapause conditions and compared to 1-week-old flies in different behavioral assays of sleep, negative geotaxis and exploratory walking. We found that the senescence of geotaxis and locomotor behavior seen under normal rearing conditions was negligible in flies kept in dormancy. The normal senescence of rhythmic activity and sleep patterns during the daytime was also reduced by adult dormancy. Investigating the morphology of specific neuromuscular junctions (NMJs), we found that changes normally seen with aging do not take place in dormant flies. To monitor age-associated changes in neuronal circuits regulating activity rhythms, sleep and walking behavior we applied antisera to tyrosine hydroxylase (TH), serotonin and several neuropeptides to examine changes in expression levels and neuron morphology. In most neuron types the levels of stored neuromodulators decreased during normal aging, but not in diapause treated flies. No signs of neurodegeneration were seen in either condition. Our data suggest that age-related changes in motor neurons could be the cause of part of the behavioral senescence and that this is ameliorated by reproductive diapause. Earlier studies established a link between age-associated decreases in neuromodulator levels and behavioral decline that could be rescued by overexpression of neuromodulator. Thus, it is likely that the retained levels of neuromodulators in dormant flies alleviate behavioral senescence.

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“…Moreover, binding of D-serine to GluD2 leads to the acquisition of motor learning in mice [62]. Recently, it has been reported that the age-dependent increase in pyruvate carboxylase activity in glial cells causes a decrease in the level of D-serine, leading to age-related memory impairment in flies [63]. Pyruvate carboxylase generates oxaloacetic acid, which can be converted to aspartic acid.…”

Section: D-serinementioning

confidence: 99%

D-Amino Acids in the Nervous and Endocrine Systems

Kiriyama

Nochi

2016

Scientifica

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Amino acids are important components for peptides and proteins and act as signal transmitters. Only L-amino acids have been considered necessary in mammals, including humans. However, diverse D-amino acids, such as D-serine, D-aspartate, D-alanine, and D-cysteine, are found in mammals. Physiological roles of these D-amino acids not only in the nervous system but also in the endocrine system are being gradually revealed. N-Methyl-D-aspartate (NMDA) receptors are associated with learning and memory. D-Serine, D-aspartate, and D-alanine can all bind to NMDA receptors. H2S generated from D-cysteine reduces disulfide bonds in receptors and potentiates their activity. Aberrant receptor activity is related to diseases of the central nervous system (CNS), such as Alzheimer's disease, amyotrophic lateral sclerosis, and schizophrenia. Furthermore, D-amino acids are detected in parts of the endocrine system, such as the pineal gland, hypothalamus, pituitary gland, pancreas, adrenal gland, and testis. D-Aspartate is being investigated for the regulation of hormone release from various endocrine organs. Here we focused on recent findings regarding the synthesis and physiological functions of D-amino acids in the nervous and endocrine systems.

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Glial Dysfunction Causes Age-Related Memory Impairment in Drosophila

Cited by 53 publications

References 54 publications

TRAP-seq Profiling and RNAi-Based Genetic Screens Identify Conserved Glial Genes Required for Adult Drosophila Behavior

TRAP-seq Profiling and RNAi-Based Genetic Screens Identify Conserved Glial Genes Required for Adult Drosophila Behavior

Behavioral Senescence and Aging-Related Changes in Motor Neurons and Brain Neuromodulator Levels Are Ameliorated by Lifespan-Extending Reproductive Dormancy in Drosophila

D-Amino Acids in the Nervous and Endocrine Systems

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