Synaptic Pruning by Microglia in Epilepsy

Andoh, Megumi; Ikegaya, Yuji; Koyama, Ryuta

doi:10.3390/jcm8122170

Cited by 76 publications

(66 citation statements)

References 119 publications

(146 reference statements)

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“…These findings suggested that microglial activation increases following a single seizure and might contribute to further epileptogenesis. In fact, microglia promote development and aggravation of epilepsy by aberrant synaptic pruning and changes in the neuronal network [ 36 , 37 ]. In addition, Webster et al have reported an age-specific vulnerability to seizures and inflammatory stimuli in children [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical evaluation of neuroinflammation in child-onset focal epilepsy: a translocator protein PET study

Kagitani‐Shimono

Kato

Kuwayama

et al. 2021

J Neuroinflammation

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Background Neuroinflammation is associated with various chronic neurological diseases, including epilepsy; however, neuroimaging approaches for visualizing neuroinflammation have not been used in the clinical routine yet. In this study, we used the translocator protein positron emission tomography (PET) with [11C] DPA713 to investigate neuroinflammation in the epileptogenic zone in patients with child-onset focal epilepsy. Methods Patients with intractable focal epilepsy were recruited at the Epilepsy Center of Osaka University; those who were taking any immunosuppressants or steroids were excluded. PET images were acquired for 60 min after intravenous administration of [11C] DPA713. The PET image of [11C] DPA713 was co-registered to individual’s magnetic resonance imaging (MRI), and the standardized uptake value ratio (SUVr) in regions of interest, which were created in non-lesions and lesions, was calculated using the cerebellum as a pseudo-reference region. In the case of epilepsy surgery, the correlation between SUVr in lesions and pathological findings was analyzed. Results Twenty-seven patients (mean age: 11.3 ± 6.2 years, male/female: 17/10) were included in this study. Of these, 85.1% showed increased uptake of [11C] DPA713 in the focal epileptic lesion. Three patients showed epileptic spasms, suggesting partial seizure onset, and all 18 patients with abnormal lesions on MRI were similarly highlighted by significant uptake of [11C] DPA713. DPA713-positive patients had a broad range of etiologies, including focal cortical dysplasia, tumors, infarction, and hippocampal sclerosis. Five out of nine MRI-negative patients showed abnormal [11C] DPA713 uptake. The SUVr of [11C] DPA713 in lesions was significantly higher than that in non-lesions. In seven patients who underwent epilepsy surgery, increased [11C] DPA713 uptake was associated with microglial activation. Conclusions This study indicates that [11C] DPA713 uptake has valuable sensitivity in the identification of epileptic foci in child-onset focal epilepsy, and inflammation is implicated in the pathophysiology in the epileptic foci caused by various etiologies. Further research is required to establish diagnostic tools for identifying focal epileptogenic zones.

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Section: Discussionmentioning

confidence: 99%

Clinical evaluation of neuroinflammation in child-onset focal epilepsy: a translocator protein PET study

Kagitani‐Shimono

Kato

Kuwayama

et al. 2021

J Neuroinflammation

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“…Glial cells in the brain could respond to various stimuli and the status of these cells is highly associated with neuronal activity [ 18 , 19 , 20 ]. In this study, the index of neuronal activity, c-fos expression, was robustly elevated in the DG of PTZ-exposed control mice, but not in Fb Ctgf KO mice.…”

Section: Discussionmentioning

confidence: 99%

“…Given the deletion of Ctgf was only operated in forebrain excitatory neurons, we believed the activation of microglia is resulted from PTZ-enhanced neuronal activity. Microglial activation may augment synaptic pruning, alter synaptic transmission and excitation/inhibition balance that lead to the development and aggravation of epilepsy [20]. Reactive microglia were noted in postmortem brain samples of patients with epileptic seizures and animal models of epilepsy [53].…”

Section: Glial Reaction and Epilepsymentioning

confidence: 99%

“…Glial cells constitute the majority of cell population in the nervous system and play important roles in its structural development and functional maintenance. The statuses of astrocytes and microglia are closely related to neuronal activity [ 18 , 19 ] and have been associated with epileptogenesis [ 20 , 21 , 22 , 23 , 24 , 25 ]. Since Ctgf is expressed exclusively in the excitatory neurons in the mouse brain [ 17 ], our Fb Ctgf KO mouse model provides an excellent opportunity to explore the interactions between neurons and glia in the pathophysiology of epilepsy [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Mice Lacking Connective Tissue Growth Factor in the Forebrain Exhibit Delayed Seizure Response, Reduced C-Fos Expression and Different Microglial Phenotype Following Acute PTZ Injection

Siow

Tsao

Chang

et al. 2020

IJMS

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Connective tissue growth factor (CTGF) plays important roles in the development and regeneration of the connective tissue, yet its function in the nervous system is still not clear. CTGF is expressed in some distinct regions of the brain, including the dorsal endopiriform nucleus (DEPN) which has been recognized as an epileptogenic zone. We generated a forebrain-specific Ctgf knockout (FbCtgf KO) mouse line in which the expression of Ctgf in the DEPN is eliminated. In this study, we adopted a pentylenetetrazole (PTZ)-induced seizure model and found similar severity and latencies to death between FbCtgf KO and WT mice. Interestingly, there was a delay in the seizure reactions in the mutant mice. We further observed reduced c-fos expression subsequent to PTZ treatment in the KO mice, especially in the hippocampus. While the densities of astrocytes and microglia in the hippocampus were kept constant after acute PTZ treatment, microglial morphology was different between genotypes. Our present study demonstrated that in the FbCtgf KO mice, PTZ failed to increase neuronal activity and microglial response in the hippocampus. Our results suggested that inhibition of Ctgf function may have a therapeutic potential in preventing the pathophysiology of epilepsy.

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“…Activated microglia also regulate synaptic activity by engulfing pre-or post-synapses. This aberrant microglia-dependent synaptic pruning changes the excitation/inhibition balance of neurons toward excitation, which leads to the development and aggravation of epilepsy [7]. Furthermore, activated microglia leads to the recruitment of neutrophils and monocytes from blood into the brain parenchyma by various chemokines such as monocyte chemotactic protein-1 (MCP-1) that is a primary chemokine to recruit monocyte/macrophage-mediated by C-C motif chemokine receptor 2 (CCR2) [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

CDDO-Me Inhibits Microglial Activation and Monocyte Infiltration by Abrogating NFκB- and p38 MAPK-Mediated Signaling Pathways Following Status Epilepticus

Kim

Park

Lee

et al. 2020

Cells

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Following status epilepticus (SE, a prolonged seizure activity), microglial activation, and monocyte infiltration result in the inflammatory responses in the brain that is involved in the epileptogenesis. Therefore, the regulation of microglia/monocyte-mediated neuroinflammation is one of the therapeutic strategies for avoidance of secondary brain injury induced by SE. 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me; RTA 402) is an activator of nuclear factor-erythroid 2-related factor 2 (Nrf2), which regulates intracellular redox homeostasis. In addition, CDDO-Me has anti-inflammatory properties that suppress microglial proliferation and its activation, although the underlying mechanisms have not been clarified. In the present study, CDDO-Me ameliorated monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC) following SE, accompanied by abrogating monocyte chemotactic protein-1 (MCP-1)/tumor necrosis factor-α (TNF-α) expressions and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. Furthermore, CDDO-Me inhibited nuclear factor-κB (NFκB)-S276 phosphorylation and microglial transformation, independent of Nrf2 expression. Similar to CDDO-Me, SN50 (an NFκB inhibitor) mitigated monocyte infiltration by reducing MCP-1 and p38 MAPK phosphorylation in the FPC following SE. Therefore, these findings suggest, for the first time, that CDDO-Me may attenuate microglia/monocyte-mediated neuroinflammation via modulating NFκB- and p38 MAPK-MCP-1 signaling pathways following SE.

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Synaptic Pruning by Microglia in Epilepsy

Cited by 76 publications

References 119 publications

Clinical evaluation of neuroinflammation in child-onset focal epilepsy: a translocator protein PET study

Clinical evaluation of neuroinflammation in child-onset focal epilepsy: a translocator protein PET study

Mice Lacking Connective Tissue Growth Factor in the Forebrain Exhibit Delayed Seizure Response, Reduced C-Fos Expression and Different Microglial Phenotype Following Acute PTZ Injection

CDDO-Me Inhibits Microglial Activation and Monocyte Infiltration by Abrogating NFκB- and p38 MAPK-Mediated Signaling Pathways Following Status Epilepticus

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