The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex

Zhang, Bo; Zou, Jia; Han, Lirong; Beeler, Brennan; Friedman, Joseph L.; Griffin, Elizabeth; Piao, Yue Shan; Rensing, Nicholas; Wong, Michael

doi:10.1111/epi.14526

Cited by 32 publications

(36 citation statements)

References 34 publications

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“…Therefore, they concluded that the effects seen in Tsc1 CX3CR1 mice were not exclusively driven by reactive microglia but could also be elicited by affected neurons and astrocytes. Furthermore, post-natal induction of the knockout, which had a higher specificity for microglia showing only 5% of non-microglial cells affected, did not result in spontaneous ictal activity (218), in contrast to the previous study (217). These studies emphasize that it is essential to precisely target and characterize cell types in TSC KO models, as only small percentages of affected neurons can lead to increased neuronal excitability (219).…”

Section: Microgliamentioning

confidence: 78%

“…All of the Tsc1 CX3CR1 mice developed spontaneous recurrent seizures around 5 weeks of age, as well as two-thirds of the post-natally induced conditional knockout mice. However, that same year, Zhang et al (218) reported that CX3CR1-Cre driver lines in Tsc1 CX3CR1 animals target not solely the alleged microglia cells, but also NeuN-and rarely GFAP-positive cells. Therefore, they concluded that the effects seen in Tsc1 CX3CR1 mice were not exclusively driven by reactive microglia but could also be elicited by affected neurons and astrocytes.…”

Section: Microgliamentioning

confidence: 99%

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Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

et al. 2020

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Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation.

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Section: Microgliamentioning

confidence: 78%

Section: Microgliamentioning

confidence: 99%

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

et al. 2020

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“…To date, different CX3CR1-Cre lines have been developed and widely used in a number of studies, focusing on the roles of microglia in the CNS (Parkhurst et al, 2013;Peng et al, 2016). However, it is also reported that some CX3CR1-Cre lines have a possibility for leakage of Cre expression into other cells, such as neurons and astrocytes (Hwang et al, 2017;Zhang et al, 2018). Zhao et al was neither observed in neurons nor in astrocytes in CX3CR1-Cre mice obtained from MMRRC (#036395) and concluded that the line was microglia-specific (Zhao et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic Regulation of CX3CR1-Expressing Microglia Using Gi-DREADD Exerts Sex-Dependent Anti-Allodynic Effects in Mouse Models of Neuropathic Pain

et al. 2020

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Despite growing evidence suggesting that spinal microglia play an important role in the molecular mechanism underlying experimental neuropathic pain (NP) in male rodents, evidence regarding the sex-dependent role of these microglia in NP is insufficient. In this study, we evaluated the effects of microglial regulation on NP using Gi-designer receptors exclusively activated by designer drugs (Gi-DREADD) driven by the microglia-specific Cx3cr1 promoter. For the Cre-dependent expression of human Gi-coupled M4 muscarinic receptors (hM4Di) in CX3C chemokine receptor 1-expressing (CX3CR1 +) cells, R26-LSL-hM4Di-DREADD mice were crossed with CX3CR1-Cre mice. Mouse models of NP were generated by partial sciatic nerve ligation (PSL) and treatment with anti-cancer agent paclitaxel (PTX) or oxaliplatin (OXA), and mechanical allodynia was evaluated using the von Frey test. Immunohistochemistry revealed that hM4Di was specifically expressed on Iba1 + microglia, but not on astrocytes or neurons in the spinal dorsal horn of CX3CR1-hM4Di mice. PSL-induced mechanical allodynia was significantly attenuated by systemic (intraperitoneal, i.p.) administration of 10 mg/kg of clozapine Noxide (CNO), a hM4Di-selective ligand, in male CX3CR1-hM4Di mice. The mechanical threshold in naive CX3CR1-hM4Di mice was not altered by i.p. administration of CNO. Consistently, local (intrathecal, i.t.) administration of CNO (20 nmol) significantly relieved PSL-induced mechanical allodynia in male CX3CR1-hM4Di mice. However, neither i.p. nor i.t. administration of CNO affected PSL-induced mechanical allodynia in female CX3CR1-hM4Di mice. Both i.p. and i.t. administration of CNO relieved PTX-induced mechanical allodynia in male CX3CR1-hM4Di mice, and a limited effect of i.p. CNO was observed in female CX3CR1-hM4Di mice. Unlike PTX-induced allodynia, OXA-induced mechanical allodynia was slightly improved, but not significantly relieved, by i.p. administration of CNO in both male and female CX3CR1-hM4Di mice. These results suggest that spinal microglia can be regulated by Gi-DREADD and support the notion that

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“…More recent studies in TSC mouse models point to a possible role for microglia abnormalities (resulting from Tsc1 inactivation) in contributing to epileptogenesis; however, whether microglial cells are primary contributors to epilepsy and associated comorbidities is still matter of discussion (Zhang et al. ; Zhao et al. ).…”

Section: What We Have Learned So Farmentioning

confidence: 99%

New insights into a spectrum of developmental malformations related tomTORdysregulations: challenges and perspectives

et al. 2019

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In recent years the role of the mammalian target of rapamycin (mTOR) pathway has emerged as crucial for normal cortical development. Therefore, it is not surprising that aberrant activation of mTOR is associated with developmental malformations and epileptogenesis. A broad spectrum of malformations of cortical development, such as focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC), have been linked to either germline or somatic mutations in mTOR pathway-related genes, commonly summarised under the umbrella term 'mTORopathies'. However, there are still a number of unanswered questions regarding the involvement of mTOR in the pathophysiology of these abnormalities. Therefore, a monogenetic disease, such as TSC, can be more easily applied as a model to study the mechanisms of epileptogenesis and identify potential new targets of therapy. Developmental neuropathology and genetics demonstrate that FCD IIb and hemimegalencephaly are the same diseases. Constitutive activation of mTOR signalling represents a shared pathogenic mechanism in a group of developmental malformations that have histopathological and clinical features in common, such as epilepsy, autism and other comorbidities. We seek to understand the effect of mTOR dysregulation in a developing cortex with the propensity to generate seizures as well as the aftermath of the surrounding environment, including the white matter.

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The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex

Cited by 32 publications

References 34 publications

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

Chemogenetic Regulation of CX3CR1-Expressing Microglia Using Gi-DREADD Exerts Sex-Dependent Anti-Allodynic Effects in Mouse Models of Neuropathic Pain

New insights into a spectrum of developmental malformations related tomTORdysregulations: challenges and perspectives

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