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  1. Article: Remembering and forgetting in sleep: Selective synaptic plasticity during sleep driven by scaling factors Homer1a and Arc.

    Diering, Graham H

    Neurobiology of stress

    2022  Volume 22, Page(s) 100512

    Abstract: Sleep is a conserved and essential process that supports learning and memory. Synapses are a major target of sleep function and a locus of sleep need. Evidence in the literature suggests that the need for sleep has a cellular or microcircuit level basis, ...

    Abstract Sleep is a conserved and essential process that supports learning and memory. Synapses are a major target of sleep function and a locus of sleep need. Evidence in the literature suggests that the need for sleep has a cellular or microcircuit level basis, and that sleep need can accumulate within localized brain regions as a function of waking activity. Activation of sleep promoting kinases and accumulation of synaptic phosphorylation was recently shown to be part of the molecular basis for the localized sleep need. A prominent hypothesis in the field suggests that some benefits of sleep are mediated by a broad but selective weakening, or scaling-down, of synaptic strength during sleep in order to offset increased excitability from synaptic potentiation during wake. The literature also shows that synapses can be strengthened during sleep, raising the question of what molecular mechanisms may allow for selection of synaptic plasticity types during sleep. Here I describe mechanisms of action of the scaling factors Arc and Homer1a in selective plasticity and links with sleep need. Arc and Homer1a are induced in neurons in response to waking neuronal activity and accumulate with time spent awake. I suggest that during sleep, Arc and Homer1a drive broad weakening of synapses through homeostatic scaling-down, but in a manner that is sensitive to the plasticity history of individual synapses, based on patterned phosphorylation of synaptic proteins. Therefore, Arc and Homer1a may offer insights into the intricate links between a cellular basis of sleep need and memory consolidation during sleep.
    Language English
    Publishing date 2022-12-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2816500-7
    ISSN 2352-2895
    ISSN 2352-2895
    DOI 10.1016/j.ynstr.2022.100512
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Sleep on it.

    Diering, Graham H

    Science (New York, N.Y.)

    2017  Volume 358, Issue 6362, Page(s) 457

    Language English
    Publishing date 2017-10-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aap9536
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Evaluating Fatty Acid Amide Hydrolase as a Suitable Target for Sleep Promotion in a Transgenic TauP301S Mouse Model of Neurodegeneration.

    Martin, Shenée C / Joyce, Kathryn K / Harper, Kathryn M / Harp, Samuel J / Cohen, Todd J / Moy, Sheryl S / Diering, Graham H

    Pharmaceuticals (Basel, Switzerland)

    2024  Volume 17, Issue 3

    Abstract: Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer's disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain ... ...

    Abstract Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer's disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting AD progression. However, commonly used sleep aid medications are associated with an increased risk of AD, highlighting the need for sleep aids with novel mechanisms of action. The endocannabinoid system holds promise as a potentially effective and novel sleep-enhancing target. By using pharmacology and genetic knockout strategies, we evaluated fatty acid amide hydrolase (FAAH) as a therapeutic target to improve sleep and halt disease progression in a transgenic Tau P301S (PS19) model of Tauopathy and AD. We have recently shown that PS19 mice exhibit sleep disruption in the form of dark phase hyperarousal as an early symptom that precedes robust Tau pathology and cognitive decline. Acute FAAH inhibition with PF3845 resulted in immediate improvements in sleep behaviors in male and female PS19 mice, supporting FAAH as a potentially suitable sleep-promoting target. Moreover, sustained drug dosing for 5-10 days resulted in maintained improvements in sleep. To evaluate the effect of chronic FAAH inhibition as a possible therapeutic strategy, we generated FAAH-/- PS19 mice models. Counter to our expectations, FAAH knockout did not protect PS19 mice from progressive sleep loss, neuroinflammation, or cognitive decline. Our results provide support for FAAH as a novel target for sleep-promoting therapies but further indicate that the complete loss of FAAH activity may be detrimental.
    Language English
    Publishing date 2024-02-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph17030319
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The E3 ubiquitin ligase TRIM9 regulates synaptic function and actin dynamics in response to netrin-1.

    McCormick, Laura E / Evans, Elliot B / Barker, Natalie K / Herring, Laura E / Diering, Graham H / Gupton, Stephanie L

    Molecular biology of the cell

    2024  Volume 35, Issue 5, Page(s) ar67

    Abstract: During neuronal development, dynamic filopodia emerge from dendrites and mature into functional dendritic spines during synaptogenesis. Dendritic filopodia and spines respond to extracellular cues, influencing dendritic spine shape and size as well as ... ...

    Abstract During neuronal development, dynamic filopodia emerge from dendrites and mature into functional dendritic spines during synaptogenesis. Dendritic filopodia and spines respond to extracellular cues, influencing dendritic spine shape and size as well as synaptic function. Previously, the E3 ubiquitin ligase TRIM9 was shown to regulate filopodia in early stages of neuronal development, including netrin-1-dependent axon guidance and branching. Here, we demonstrate that TRIM9 also localizes to dendritic filopodia and spines of murine cortical and hippocampal neurons during synaptogenesis and is required for synaptic responses to netrin. In particular, TRIM9 is enriched in the postsynaptic density (PSD) within dendritic spines and loss of
    MeSH term(s) Mice ; Animals ; Actins/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Netrin-1 ; Neurons/metabolism ; Hippocampus/metabolism ; Dendritic Spines/metabolism ; Nerve Tissue Proteins/metabolism
    Chemical Substances Actins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Netrin-1 (158651-98-0) ; Trim9 protein, mouse (EC 2.3.2.27) ; Nerve Tissue Proteins
    Language English
    Publishing date 2024-03-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E23-12-0476
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: The E3 ubiquitin ligase TRIM9 regulates synaptic function and actin dynamics.

    McCormick, Laura E / Evans, Elliot B / Barker, Natalie K / Herring, Laura E / Diering, Graham H / Gupton, Stephanie L

    bioRxiv : the preprint server for biology

    2024  

    Abstract: During neuronal development, dynamic filopodia emerge from dendrites and mature into functional dendritic spines during synaptogenesis. Dendritic filopodia and spines respond to extracellular cues, influencing dendritic spine shape and size as well as ... ...

    Abstract During neuronal development, dynamic filopodia emerge from dendrites and mature into functional dendritic spines during synaptogenesis. Dendritic filopodia and spines respond to extracellular cues, influencing dendritic spine shape and size as well as synaptic function. Previously, the E3 ubiquitin ligase TRIM9 was shown to regulate filopodia in early stages of neuronal development, including netrin-1 dependent axon guidance and branching. Here we demonstrate TRIM9 also localizes to dendritic filopodia and spines of murine cortical and hippocampal neurons during synaptogenesis and is required for synaptic responses to netrin. In particular, TRIM9 is enriched in the post-synaptic density (PSD) within dendritic spines and loss of
    Language English
    Publishing date 2024-01-01
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.31.573790
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The AMPA Receptor Code of Synaptic Plasticity.

    Diering, Graham H / Huganir, Richard L

    Neuron

    2018  Volume 100, Issue 2, Page(s) 314–329

    Abstract: Changes in the properties and postsynaptic abundance of AMPA-type glutamate receptors (AMPARs) are major mechanisms underlying various forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic ... ...

    Abstract Changes in the properties and postsynaptic abundance of AMPA-type glutamate receptors (AMPARs) are major mechanisms underlying various forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic scaling. The function and the trafficking of AMPARs to and from synapses is modulated by specific AMPAR GluA1-GluA4 subunits, subunit-specific protein interactors, auxiliary subunits, and posttranslational modifications. Layers of regulation are added to AMPAR tetramers through these different interactions and modifications, increasing the computational power of synapses. Here we review the reliance of synaptic plasticity on AMPAR variants and propose "the AMPAR code" as a conceptual framework. The AMPAR code suggests that AMPAR variants will be predictive of the types and extent of synaptic plasticity that can occur and that a hierarchy exists such that certain AMPARs will be disproportionally recruited to synapses during LTP/homeostatic scaling up, or removed during LTD/homeostatic scaling down.
    MeSH term(s) Animals ; Brain/physiology ; Humans ; Neuronal Plasticity/physiology ; Receptors, AMPA/physiology ; Synapses/physiology
    Chemical Substances Receptors, AMPA
    Language English
    Publishing date 2018-10-24
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2018.10.018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Sleep disruption precedes forebrain synaptic Tau burden and contributes to cognitive decline in a sex-dependent manner in the P301S Tau transgenic mouse model.

    Martin, Shenee C / Joyce, Kathryn K / Harper, Kathryn M / Nikolova, Viktoriya D / Cohen, Todd J / Moy, Sheryl S / Diering, Graham H

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Background: Sleep is an essential process that supports brain health and cognitive function in part through the modification of neuronal synapses. Sleep disruption, and impaired synaptic processes, are common features in neurodegenerative diseases, ... ...

    Abstract Background: Sleep is an essential process that supports brain health and cognitive function in part through the modification of neuronal synapses. Sleep disruption, and impaired synaptic processes, are common features in neurodegenerative diseases, including Alzheimer's disease (AD). However, the casual role of sleep disruption in disease progression is not clear. Neurofibrillary tangles, made from hyperphosphorylated and aggregated Tau protein, form one of the major hallmark pathologies seen in AD and contribute to cognitive decline, synapse loss and neuronal death.Tau has been shown to aggregate in synapses which may impair restorative synapse processes occurring during sleep. However, it remains unclear how sleep disruption and synaptic Tau pathology interact to drive cognitive decline. It is also unclear whether the sexes show differential vulnerability to the effects of sleep loss in the context of neurodegeneration.
    Methods: We used a piezoelectric home-cage monitoring system to measure sleep behavior in 3-11month-old transgenic hTau P301S Tauopathy model mice (PS19) and littermate controls of both sexes. Subcellular fractionation and Western blot was used to examine Tau pathology in mouse forebrain synapse fractions. To examine the role of sleep disruption in disease progression, mice were exposed to acute or chronic sleep disruption. The Morris water maze test was used to measure spatial learning and memory performance.
    Results: PS19 mice exhibited a selective loss of sleep during the dark phase, referred to as hyperarousal, as an early symptom with an onset of 3months in females and 6months in males. At 6months, forebrain synaptic Tau burden did not correlate with sleep measures and was not affected by acute or chronic sleep disruption. Chronic sleep disruption accelerated the onset of decline of hippocampal spatial memory in PS19 males, but not females.
    Conclusions: Dark phase hyperarousal is an early symptom in PS19 mice that precedes robust Tau aggregation. We find no evidence that sleep disruption is a direct driver of Tau pathology in the forebrain synapse. However, sleep disruption synergized with Tau pathology to accelerate the onset of cognitive decline in males. Despite the finding that hyperarousal appears earlier in females, female cognition was resilient to the effects of sleep disruption.
    Language English
    Publishing date 2023-06-09
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.06.07.544101
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Homer1a and mGluR1/5 Signaling in Homeostatic Sleep Drive and Output.

    Martin, Shenée C / Monroe, Sarah K / Diering, Graham H

    The Yale journal of biology and medicine

    2019  Volume 92, Issue 1, Page(s) 93–101

    Abstract: Sleep is an essential physiological behavior that promotes cognitive development and function. Although the switch between sleep/wake cycles is controlled by specific neural circuits, sleep need and the restorative benefits of sleep are likely controlled ...

    Abstract Sleep is an essential physiological behavior that promotes cognitive development and function. Although the switch between sleep/wake cycles is controlled by specific neural circuits, sleep need and the restorative benefits of sleep are likely controlled by cellular mechanisms localized in critical areas of the brain involved in learning and memory including the cortex and hippocampus. However, the molecular basis for the restorative function(s) of sleep that support cognition, or for the homeostatic build-up of sleep need are poorly understood. Synapses undergo local and global changes in strength to support learning and memory and are likely a point of restoration during sleep. Homer1a and mGluR1/5, recently implicated in sleep function, are molecules involved in the scaling down process that weakens synapses during sleep to restore synapse homeostasis. During wake, long-form Homer proteins tether mGluR1/5 to IP3R and to the post-synaptic density (PSD). During sleep, short-form Homer1a uncouples mGluR1/5 from IP3R leaving mGluR1/5 open to interact with other effectors, switching mGluR1/5 signaling from "awake-type" to "sleep-type" signaling modes. Importantly, mGluR1/5 have been implicated in several neurological and neurodevelopmental disorders such as Alzheimer's disease (AD) and autism spectrum disorder (ASD), all of which show abnormal sleep phenotypes, linking sleep, disease, and mGluR1/5 signaling. Further investigation into the downstream effectors of mGluR1/5 and sleep/wake signaling will lead to more targeted therapeutic interventions.
    MeSH term(s) Animals ; Homeostasis/physiology ; Homer Scaffolding Proteins/metabolism ; Humans ; Neuronal Plasticity ; Receptors, Metabotropic Glutamate/metabolism ; Signal Transduction ; Sleep/physiology
    Chemical Substances Homer Scaffolding Proteins ; Receptors, Metabotropic Glutamate ; metabotropic glutamate receptor type 1
    Language English
    Publishing date 2019-03-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 200515-3
    ISSN 1551-4056 ; 0044-0086
    ISSN (online) 1551-4056
    ISSN 0044-0086
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Developing forebrain synapses are uniquely vulnerable to sleep loss.

    Gay, Sean M / Chartampila, Elissavet / Lord, Julia S / Grizzard, Sawyer / Maisashvili, Tekla / Ye, Michael / Barker, Natalie K / Mordant, Angie L / Mills, C Allie / Herring, Laura E / Diering, Graham H

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic ... ...

    Abstract Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long lasting changes in adult behavior. Different plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21-28), adolescent (P42-49) and adult (P70-100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition test. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of peri-neuronal nets. Our analysis further reveals the developing synapse as a convergent node between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing mechanistic insights for ASD susceptibility.
    Language English
    Publishing date 2024-04-12
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.06.565853
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Tonic endocannabinoid signaling supports sleep through development in both sexes.

    Martin, Shenée C / Gay, Sean M / Armstrong, Michael L / Pazhayam, Nila M / Reisdorph, Nichole / Diering, Graham H

    Sleep

    2022  Volume 45, Issue 8

    Abstract: Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in ... ...

    Abstract Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in juvenile and adolescent mice of both sexes. We find that eCBs lack a daily rhythm in juvenile mice, while in adolescents AEA and related oleoyl ethanolamide are increased during the sleep phase in a circadian manner. Next, we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a noninvasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark-phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep-promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.
    MeSH term(s) Animals ; Endocannabinoids/metabolism ; Endocannabinoids/pharmacology ; Female ; Male ; Mice ; Signal Transduction ; Sleep ; Synapses/physiology ; Synaptic Transmission
    Chemical Substances Endocannabinoids
    Language English
    Publishing date 2022-04-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 424441-2
    ISSN 1550-9109 ; 0161-8105
    ISSN (online) 1550-9109
    ISSN 0161-8105
    DOI 10.1093/sleep/zsac083
    Database MEDical Literature Analysis and Retrieval System OnLINE

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