Cross-talk between GABAergic postsynapse and microglia regulate synapse loss after brain ischemia

Cramer, Teresa; Gill, Raminder; Thirouin, Zahra S.; Vaas, Markus; Sampath, Suchita; Martineau, Fanny; Noya, Sara B.; Panzanelli, Patrizia; Sudharshan, Tania J J; Colameo, David; Chang, Philip K.-Y.; Wu, Pei You; Shi, Roy; Barker, Philip A.; Brown, Steven A.; Paolicelli, Rosa Chiara; Klohs, Jan; McKinney, R. Anne; Tyagarajan, Shiva K.

doi:10.1126/sciadv.abj0112

Cited by 37 publications

(15 citation statements)

References 62 publications

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“…Notably, we found a dendritic spine loss in all layers over time irrespective of the lesioned pathway, with more pronounced effects in the denervated layers. In this context, it is interesting to theorize that specific subpopulations of spines across layers are targets for homeostatic synaptic plasticity, e.g., through microglia-synapse interactions ( Cramer et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Denervated mouse CA1 pyramidal neurons express homeostatic synaptic plasticity following entorhinal cortex lesion

Lenz

Eichler

Kruse

et al. 2023

Front. Mol. Neurosci.

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Structural, functional, and molecular reorganization of denervated neural networks is often observed in neurological conditions. The loss of input is accompanied by homeostatic synaptic adaptations, which can affect the reorganization process. A major challenge of denervation-induced homeostatic plasticity operating in complex neural networks is the specialization of neuronal inputs. It remains unclear whether neurons respond similarly to the loss of distinct inputs. Here, we used in vitro entorhinal cortex lesion (ECL) and Schaffer collateral lesion (SCL) in mouse organotypic entorhino-hippocampal tissue cultures to study denervation-induced plasticity of CA1 pyramidal neurons. We observed microglia accumulation, presynaptic bouton degeneration, and a reduction in dendritic spine numbers in the denervated layers 3 days after SCL and ECL. Transcriptome analysis of the CA1 region revealed complex changes in differential gene expression following SCL and ECL compared to non-lesioned controls with a specific enrichment of differentially expressed synapse-related genes observed after ECL. Consistent with this finding, denervation-induced homeostatic plasticity of excitatory synapses was observed 3 days after ECL but not after SCL. Chemogenetic silencing of the EC but not CA3 confirmed the pathway-specific induction of homeostatic synaptic plasticity in CA1. Additionally, increased RNA oxidation was observed after SCL and ECL. These results reveal important commonalities and differences between distinct pathway lesions and demonstrate a pathway-specific induction of denervation-induced homeostatic synaptic plasticity.

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Section: Discussionmentioning

confidence: 99%

Denervated mouse CA1 pyramidal neurons express homeostatic synaptic plasticity following entorhinal cortex lesion

Lenz

Eichler

Kruse

et al. 2023

Front. Mol. Neurosci.

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“…Microglia, which are derived from the yolk sac, are the primary resident mononuclear macrophages in the retina and are regarded as the first line of active immune defenders. They express many pattern recognition receptors and immune receptors, such as AT1R , AT2R , and TβRII , empowering their function of guiding blood vessel formation, guaranteeing the survival of neurons, monitoring neuronal activity, pruning synapses of neurons, sustaining density of dendritic spines and clearing apoptotic cells or protein aggregates ( Takahashi et al, 2005 ; Parkhurst et al, 2013 ; Cramer et al, 2022 ; He et al, 2022 ; Figure 1 ). Retinal microglia mainly present high branch structures to guarantee retinal homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

Feng

Qin

et al. 2023

Front. Mol. Neurosci.

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Microglia are the primary resident retinal macrophages that monitor neuronal activity in real-time and facilitate angiogenesis during retinal development. In certain retinal diseases, the activated microglia promote retinal angiogenesis in hypoxia stress through neurovascular coupling and guide neovascularization to avascular areas (e.g., the outer nuclear layer and macula lutea). Furthermore, continuously activated microglia secrete inflammatory factors and expedite the loss of the blood-retinal barrier which causes irreversible damage to the secondary death of neurons. In this review, we support microglia can be a potential cellular therapeutic target in retinopathy. We briefly describe the relevance of microglia to the retinal vasculature and blood-retinal barrier. Then we discuss the signaling pathway related to how microglia move to their destinations and regulate vascular regeneration. We summarize the properties of microglia in different retinal disease models and propose that reducing the number of pro-inflammatory microglial death and conversing microglial phenotypes from pro-inflammatory to anti-inflammatory are feasible for treating retinal neovascularization and the damaged blood-retinal barrier (BRB). Finally, we suppose that the unique properties of microglia may aid in the vascularization of retinal organoids.

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“…Further studies using isoform-specific DARPin clones to capture gephyrin protein networks in neuronal compared to non-neuronal cells will clarify which protein interactors may be isoform or cell type specific. Indeed our group recently demonstrated gephyrin affects microglial reactivity and synapse stability after stroke (Cramer et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed our group recently demonstrated gephyrin affects microglial reactivity and synapse stability after stroke (Cramer et al, 2022).…”

Section: Use Of Anti-gephyrin Darpins As Biochemical Toolsmentioning

confidence: 99%

“…https://www.isogenic.info/html/7__randomisation.html#methods C56Bl/6J mice were purchased from Charles River (Germany) and timed-pregnant Wistar rats (for E17 embryo collection for neuron culture) were purchased from Envigo (Netherlands). The S268A/S270A phospho-null mouse was previously generated using CRISPR-Cas9 editing to mutate residues at the endogenous locus (Cramer et al, 2022). The collection of embryonic and adult tissue was performed in accordance with the European Community Council Directives of November 24 th 1986 (86/609/EEC).…”

Section: Animalsmentioning

confidence: 99%

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A DARPin-based molecular toolset to probe gephyrin and inhibitory synapse biology

Campbell

Dittmann

Dreier

et al. 2022

Preprint

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Neuroscience currently requires the use of antibodies to study synaptic proteins, where antibody binding is used as a correlate to define the presence, plasticity, and regulation of synapses. Gephyrin is an inhibitory synaptic scaffolding protein used to mark GABAergic and glycinergic postsynaptic sites. Despite the importance of gephyrin in modulating inhibitory transmission, its study is currently limited by the tractability of available reagents. Designed Ankyrin Repeat Proteins (DARPins) are a class of synthetic protein binder derived from diverse libraries by in vitro selection, and tested by high-throughput screening to produce specific binders. In order to generate a functionally diverse toolset for studying inhibitory synapses, we screened a DARPin library against gephyrin mutants representing both phosphorylated and dephosphorylated states. We validated the robust use of anti-gephyrin DARPin clones for morphological identification of gephyrin clusters in rodent neuron culture and brain tissue, discovering previously overlooked clusters. This DARPin-based toolset includes clones with heterogenous gephyrin binding modes that allowed for identification of the most extensive gephyrin interactome to date, and defined novel classes of putative interactors, creating a framework for understanding gephyrin's non-synaptic functions. This study demonstrates anti-gephyrin DARPins as a versatile platform for studying inhibitory synapses in an unprecedented manner.

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Cross-talk between GABAergic postsynapse and microglia regulate synapse loss after brain ischemia

Cited by 37 publications

References 62 publications

Denervated mouse CA1 pyramidal neurons express homeostatic synaptic plasticity following entorhinal cortex lesion

Denervated mouse CA1 pyramidal neurons express homeostatic synaptic plasticity following entorhinal cortex lesion

Microglia: The breakthrough to treat neovascularization and repair blood-retinal barrier in retinopathy

A DARPin-based molecular toolset to probe gephyrin and inhibitory synapse biology

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