Differential effects of SNARE-dependent gliotransmission on behavioral phenotypes in a mouse model of Huntington's disease

King, Annesha C.; Wood, Tara; Rodriguez, Efrain; Parpura, Vladimir; Gray, Michelle

doi:10.1016/j.expneurol.2020.113358

Cited by 5 publications

(4 citation statements)

References 66 publications

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“…Whereas extrinsic signals might play a role in establishing region (or layer) specific structure difference, little is known about the role of astrocyte signaling in this dynamic interaction. To test whether astrocyte signaling is relevant for the maintenance of backbone structure, GFAP‐immunolabeled astrocytes were skeletonized in cryosections containing the dorsal hippocampus of mice lacking exocytosis‐dependent signaling in astrocytes (dnSNARE mice) (Pascual et al, 2005), which have been shown to lack SNARE‐mediated exocytosis specifically in astrocytes by different laboratories (Halassa et al, 2009; King et al, 2020; Pankratov & Lalo, 2015; Sardinha et al, 2017; Sultan et al, 2015; Zhang et al, 2004). The reconstruction of astrocyte GFAP‐immunolabeled structures in cryosections of C57BL/6J mice confirmed that the structural heterogeneity between hippocampal layers described in Figure 1 is maintained under these experimental conditions (Figure S3a–f).…”

Section: Resultsmentioning

confidence: 99%

Astrocyte structural heterogeneity in the mouse hippocampus

Viana

Machado

Abreu

et al. 2023

Glia

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Astrocytes are integral components of brain circuits, where they sense, process, and respond to surrounding activity, maintaining homeostasis and regulating synaptic transmission, the sum of which results in behavior modulation. These interactions are possible due to their complex morphology, composed of a tree-like structure of processes to cover defined territories ramifying in a mesh-like system of fine leaflets unresolved by conventional optic microscopy. While recent reports devoted more attention to leaflets and their dynamic interactions with synapses, our knowledge about the tree-like "backbone" structure in physiological conditions is incomplete.Recent transcriptomic studies described astrocyte molecular diversity, suggesting structural heterogeneity in regions such as the hippocampus, which is crucial for cognitive and emotional behaviors. In this study, we carried out the structural analysis of astrocytes across the hippocampal subfields of Cornu Ammonis area 1 (CA1) and dentate gyrus in the dorsoventral axis. We found that astrocytes display heterogeneity across the hippocampal subfields, which is conserved along the dorsoventral axis. We further found that astrocytes appear to contribute in an exocytosis-dependent manner to a signaling loop that maintains the backbone structure. These findings reveal João Filipe Viana and João Luís Machado contributed equally to this study.

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Section: Resultsmentioning

confidence: 99%

Astrocyte structural heterogeneity in the mouse hippocampus

Viana

Machado

Abreu

et al. 2023

Glia

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“…9 and Supplementary Table 2). Disruption of SNARE proteins in astrocytes by mutant Htt cause impaired gliotransmission associated with behavioral disruptions in HD model mice [224]. Evaluation of Htt protein interactors associated with SNARE vesicular transport may reveal key mechanisms underlying psychiatric and behavioral changes in HD.…”

Section: Membrane Traffickingmentioning

confidence: 99%

Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington’s Disease

Podvin

Rosenthal

Poon

et al. 2022

JHD

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Background: Huntington’s disease (HD) is a genetic neurodegenerative disease caused by trinucleotide repeat (CAG) expansions in the human HTT gene encoding the huntingtin protein (Htt) with an expanded polyglutamine tract. Objective: HD models from yeast to transgenic mice have investigated proteins interacting with mutant Htt that may initiate molecular pathways of cell death. There is a paucity of datasets of published Htt protein interactions that include the criteria of 1) defining fragments or full-length Htt forms, 2) indicating the number of poly-glutamines of the mutant and wild-type Htt forms, and 3) evaluating native Htt interaction complexes. This research evaluated such interactor data to gain understanding of Htt dysregulation of cellular pathways. Methods: Htt interacting proteins were compiled from the literature that meet our criteria and were subjected to network analysis via clustering, gene ontology, and KEGG pathways using rigorous statistical methods. Results: The compiled data of Htt interactors found that both mutant and wild-type Htt interact with more than 2,971 proteins. Application of a community detection algorithm to all known Htt interactors identified significant signal transduction, membrane trafficking, chromatin, and mitochondrial clusters, among others. Binomial analyses of a subset of reported protein interactor information determined that chromatin organization, signal transduction and endocytosis were diminished, while mitochondria, translation and membrane trafficking had enriched overall edge effects. Conclusion: The data support the hypothesis that mutant Htt disrupts multiple cellular processes causing toxicity. This dataset is an open resource to aid researchers in formulating hypotheses of HD mechanisms of pathogenesis.

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“…It is caused by the accumulation of huntingtin protein (HTT) induced by CAG expansion in the gene. It has been reported that HTT over-expression can block the assembly of SNARE complexes and SNARE complex-mediated vesicle exocytosis (93). Recent studies have indicated that the insufficient release of presynaptic neurotransmitters is characterized by changes in function and distribution, accompanied by loss of SNAP-25 and rabphilin 3a, which are involved in vesicle docking and recycling (94).…”

Section: Huntington's Diseasementioning

confidence: 99%

Research progress on vesicle cycle and neurological disorders

2021

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Neurons are special polarized cells whose synaptic vesicles release neurotransmitters into the synaptic cleft, acting on postsynaptic receptors and thus transmitting information from presynaptic to postsynaptic states. The integrity of the vesicle cycle is critical to the transmission of neural signals in the brain. According to the molecular mechanism of calcium-triggered release, the assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) is required in the process of synaptic vesicle fusion and vesicle exocytosis. Many delicate steps are required to maintain the dynamic process of ‘release-recycle’, including intermediate processes and the dynamic balance of neurotransmission. Various neurodegenerative and neuropsychiatric diseases result from synaptic cycle dysfunction. This review of the relationships between the structure and function of synaptic vesicles in physiological and pathological conditions provides a theoretical basis for synaptic transmission and a novel avenue for the study of synaptic plasticity associated with mood disorders, highlighting potential targets for treating diseases.

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Differential effects of SNARE-dependent gliotransmission on behavioral phenotypes in a mouse model of Huntington's disease

Cited by 5 publications

References 66 publications

Astrocyte structural heterogeneity in the mouse hippocampus

Astrocyte structural heterogeneity in the mouse hippocampus

Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington’s Disease

Research progress on vesicle cycle and neurological disorders

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