Microglia Depletion-Induced Remodeling of Extracellular Matrix and Excitatory Synapses in the Hippocampus of Adult Mice

Strackeljan, Luisa; Bączyńska, Ewa; Cangalaya, Carla; Baidoe-Ansah, David; Włodarczyk, Jakub; Kaushik, Rahul; Dityatev, Alexander

doi:10.3390/cells10081862

Cited by 45 publications

(33 citation statements)

References 54 publications

(79 reference statements)

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“…Upon microglial depletion with PLX5622, we found robust increases in PNN intensity in the PFC, SS Ctx, MO Ctx, and AUD Ctx, but not the CA1 region of the hippocampus, demonstrating that we had sufficient sensitivity to detect further increases in PNN intensity. These findings are supported by a study where microglial elimination with PLX3397 did not alter PNN intensity in the CA1 region 40 .…”

Section: Discussionsupporting

confidence: 72%

Cortical diurnal rhythms remain intact with microglial depletion

Barahona

Morabito

Swarup

et al. 2022

Sci Rep

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Microglia are subject to change in tandem with the endogenously generated biological oscillations known as our circadian rhythm. Studies have shown microglia harbor an intrinsic molecular clock which regulates diurnal changes in morphology and influences inflammatory responses. In the adult brain, microglia play an important role in the regulation of condensed extracellular matrix structures called perineuronal nets (PNNs), and it has been suggested that PNNs are also regulated in a circadian and diurnal manner. We sought to determine whether microglia mediate the diurnal regulation of PNNs via CSF1R inhibitor dependent microglial depletion in C57BL/6J mice, and how the absence of microglia might affect cortical diurnal gene expression rhythms. While we observe diurnal differences in microglial morphology, where microglia are most ramified at the onset of the dark phase, we do not find diurnal differences in PNN intensity. However, PNN intensity increases across many brain regions in the absence of microglia, supporting a role for microglia in the regulation of PNNs. Here, we also show that cortical diurnal gene expression rhythms are intact, with no cycling gene changes without microglia. These findings demonstrate a role for microglia in the maintenance of PNNs, but not in the maintenance of diurnal rhythms.

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Section: Discussionsupporting

confidence: 72%

Cortical diurnal rhythms remain intact with microglial depletion

Barahona

Morabito

Swarup

et al. 2022

Sci Rep

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“…Furthermore, an in vitro study revealed a disruption of perineuronal nets in cultured hippocampal neurons after an incubation with microglia conditioned medium which was accompanied by altered structural synapse numbers and electrophysiological network properties [ 305 ]. In contrast, a depletion of microglia induced more dense perineuronal nets [ 310 ]. As previously introduced, microglia and inflammatory processes are suspected to play an important role in schizophrenia.…”

Section: Interneuron-abnormalities In the Hippocampus Of Schizophreni...mentioning

confidence: 99%

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

Wegrzyn

Juckel

Faissner

2022

IJMS

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Schizophrenia is a grave neuropsychiatric disease which frequently onsets between the end of adolescence and the beginning of adulthood. It is characterized by a variety of neuropsychiatric abnormalities which are categorized into positive, negative and cognitive symptoms. Most therapeutical strategies address the positive symptoms by antagonizing D2-dopamine-receptors (DR). However, negative and cognitive symptoms persist and highly impair the life quality of patients due to their disabling effects. Interestingly, hippocampal deviations are a hallmark of schizophrenia and can be observed in early as well as advanced phases of the disease progression. These alterations are commonly accompanied by a rise in neuronal activity. Therefore, hippocampal formation plays an important role in the manifestation of schizophrenia. Furthermore, studies with animal models revealed a link between environmental risk factors and morphological as well as electrophysiological abnormalities in the hippocampus. Here, we review recent findings on structural and functional hippocampal abnormalities in schizophrenic patients and in schizophrenia animal models, and we give an overview on current experimental approaches that especially target the hippocampus. A better understanding of hippocampal aberrations in schizophrenia might clarify their impact on the manifestation and on the outcome of this severe disease.

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“…Histological analyses have revealed that activated microglia engulf damaged perineuronal nets (PNNs) in the 5xFAD brain, with PNN material identified in both mouse and human microglia [153]. Further, Strackeljan et al [154] observed that the depletion of microglia increased perisynaptic ECM proteoglycan brevican expression, accompanied by elevated expression of presynaptic marker vGluT1 and increased dendritic spine density. Collectively, these studies suggest an interplay between synaptic elements including microglia process tips, the ECM, and key molecules in glia-neuron communication, in regulating structural synaptic plasticity.…”

Section: Factors Influcening the State Of The Penta-partite Synapsementioning

confidence: 99%

Cytokine Signalling at the Microglial Penta-Partite Synapse

Aramideh

Vidal-Itriago

Morsch

et al. 2021

IJMS

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Microglial cell processes form part of a subset of synaptic contacts that have been dubbed microglial tetra-partite or quad-partite synapses. Since tetrapartite may also refer to the presence of extracellular matrix components, we propose the more precise term microglial penta-partite synapse for synapses that show a microglial cell process in close physical proximity to neuronal and astrocytic synaptic constituents. Microglial cells are now recognised as key players in central nervous system (CNS) synaptic changes. When synaptic plasticity involving microglial penta-partite synapses occurs, microglia may utilise their cytokine arsenal to facilitate the generation of new synapses, eliminate those that are not needed anymore, or modify the molecular and structural properties of the remaining synaptic contacts. In addition, microglia–synapse contacts may develop de novo under pathological conditions. Microglial penta-partite synapses have received comparatively little attention as unique sites in the CNS where microglial cells, cytokines and other factors they release have a direct influence on the connections between neurons and their function. It concerns our understanding of the penta-partite synapse where the confusion created by the term “neuroinflammation” is most counterproductive. The mere presence of activated microglia or the release of their cytokines may occur independent of inflammation, and penta-partite synapses are not usually active in a neuroimmunological sense. Clarification of these details is the main purpose of this review, specifically highlighting the relationship between microglia, synapses, and the cytokines that can be released by microglial cells in health and disease.

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Microglia Depletion-Induced Remodeling of Extracellular Matrix and Excitatory Synapses in the Hippocampus of Adult Mice

Cited by 45 publications

References 54 publications

Cortical diurnal rhythms remain intact with microglial depletion

Cortical diurnal rhythms remain intact with microglial depletion

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

Cytokine Signalling at the Microglial Penta-Partite Synapse

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