Astrocyte-dependent circuit remodeling by synapse phagocytosis

Park, Jungjoo; Chung, Won‐Suk

doi:10.1016/j.conb.2023.102732

Cited by 17 publications

(5 citation statements)

References 58 publications

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“…This phenomenon is known as the synaptic homeostasis hypothesis [51,52], and it effectively explains the changes in synaptic function and structure observed in the SD group. Another interesting hint is that the combination of SD and inflammation, the "two hits", can lead to structural and functional impairments in synapses in the hippocampus, consistent with clinical findings [51,53,54]. This reduction may be related to sleep pressure [55] and inflammation.…”

Section: Neuroinflammation Is One Of the Most Reproduced Phenomena In...mentioning

confidence: 57%

A novel two-hit insomnia and inflammation rodent model of depressive-like behaviors

Mei,

Song,

Wang

et al. 2024

Preprint

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BackgroundSystemic inflammation and insomnia often co-occur in patients with depression. However, there is no suitable animal model to investigate the relationship between inflammation, sleep deprivation (SD), and depression.MethodsTo model interactions between insomnia, inflammation, and depression, we developed a novel “two-hit” rodent model of depressive-like behaviors using continuous SD followed by daily lipopolysaccharide (LPS) treatment. Control groups received SD, LPS, or sterile phosphate-buffered salinealone. The model’s validity was assessed at the cellular and molecular levels, with fluoxetine rescue applied to confirm model validity.ResultsThe model group demonstrated significant depressive-like behaviors that were rescued by fluoxetine treatment. Transcriptomic analysis revealed alterations in neuroinflammation and synaptic plasticity pathways within the hippocampus and prefrontal cortex (PFC) of model rats. Western blotting validated alterations in key protein markers related to both processes, and immunofluorescence confirmed microglia and astrocyte activation, indicative of neuroinflammation. Additionally, transmission electron microscopy and Golgi-Cox staining revealed reduced synapse and dendritic spine density in the model group. Fluoxetine treatment reversed these structural changes. Sixteen genes associated with neuroinflammation and synaptic function were validated in human genetic studies by transcriptome-wide association analysis.ConclusionThis reliable two-hit model will be useful for investigating the roles of insomnia and inflammation in depression.

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Section: Neuroinflammation Is One Of the Most Reproduced Phenomena In...mentioning

confidence: 57%

A novel two-hit insomnia and inflammation rodent model of depressive-like behaviors

Mei,

Song,

Wang

et al. 2024

Preprint

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“…This does not rule out the possibility that, in vivo, additional mechanisms, potentially involving ECM and glial cells, may contribute to the observed Sfrp1 TG phenotype. In fact, SFRP1 mediates astrocytes-microglia cross talk 18 and both glial cell types contribute to synaptic elimination in homeostatic and pathological conditions 70,71 .…”

Section: Discussionmentioning

confidence: 99%

SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Pereyra,

Mateo,

Martin-Bermejo

et al. 2024

Preprint

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Decreased dendritic complexity and impaired synaptic function are strongly linked to cognitive decline in Alzheimer's disease (AD), and precede the emergence of other neuropathological traits that establish a harmful cycle exacerbating synaptic dysfunction. SFRP1, a glial-derived protein regulating cell-cell communication, is abnormally elevated in the brain of AD patients and related mouse models already at early disease stages. Neutralization of SFRP1 activity in mice reduces the occurrence of protein aggregates, neuroinflammation and prevents the loss of synaptic long-term potentiation (LTP). In this study, we generated transgenic mice that overexpress Sfrp1 in astrocytes to investigate whether LTP loss is due to an early influence of SFRP1 on synaptic function or results from other alterations driving disease progression. We report that SFRP1-overexpressing mice show reduced dendritic complexity and spine density in dentate gyrus granule cells during early adulthood, prior to a significant deficit in LTP response and late onset cognitive impairment. Ultrastructural analysis revealed the loss of small-sized synapses and presynaptic alterations in transgenic mice. Analysis of proteomic changes points to a general decrease in protein synthesis and modifications in the synaptic proteome, particularly of proteins related to synaptic vesicle cycle and synaptic organizers, like neurexin and neuroligin. We propose a model wherein SFRP1 directly impacts on synaptic function, by increasing the availability of synaptic organizing molecules at the synapse. These observations, combined with documented SFRP1 effects on APP processing and microglial activation, imply that SFRP1 contributes to multiple pathological effects in AD, emerging as a promising therapeutic target for this devastating disease.

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“…Lastly, we restricted our analysis to the regime where s en is sufficiently less than 1 to prevent astrocytes from effectively removing connections and switching the dense connectivity (as required in the balanced state) of our networks to one with sparse connectivity. However, since it has been shown experimentally that astrocytes are pruning synapses, through a process known as phagocytosis [ 52 , 53 ], future work should investigate how astrocytes may be modulating network dynamics by directly changing the network’s topology. Including all of these additional forms of heterogeneities, spatially, temporally, and structurally, would lead to a more robust understanding of how astrocytes are modulating network dynamics via ensheathment.…”

Section: Discussionmentioning

confidence: 99%

Investigating the ability of astrocytes to drive neural network synchrony

Handy,

Borisyuk

2023

PLoS Comput Biol

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Recent experimental works have implicated astrocytes as a significant cell type underlying several neuronal processes in the mammalian brain, from encoding sensory information to neurological disorders. Despite this progress, it is still unclear how astrocytes are communicating with and driving their neuronal neighbors. While previous computational modeling works have helped propose mechanisms responsible for driving these interactions, they have primarily focused on interactions at the synaptic level, with microscale models of calcium dynamics and neurotransmitter diffusion. Since it is computationally infeasible to include the intricate microscale details in a network-scale model, little computational work has been done to understand how astrocytes may be influencing spiking patterns and synchronization of large networks. We overcome this issue by first developing an “effective” astrocyte that can be easily implemented to already established network frameworks. We do this by showing that the astrocyte proximity to a synapse makes synaptic transmission faster, weaker, and less reliable. Thus, our “effective” astrocytes can be incorporated by considering heterogeneous synaptic time constants, which are parametrized only by the degree of astrocytic proximity at that synapse. We then apply our framework to large networks of exponential integrate-and-fire neurons with various spatial structures. Depending on key parameters, such as the number of synapses ensheathed and the strength of this ensheathment, we show that astrocytes can push the network to a synchronous state and exhibit spatially correlated patterns.

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Astrocyte-dependent circuit remodeling by synapse phagocytosis

Cited by 17 publications

References 58 publications

A novel two-hit insomnia and inflammation rodent model of depressive-like behaviors

A novel two-hit insomnia and inflammation rodent model of depressive-like behaviors

SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Investigating the ability of astrocytes to drive neural network synchrony

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