Microglial mTOR is Neuronal Protective and Antiepileptogenic in the Pilocarpine Model of Temporal Lobe Epilepsy

Zhao, Xiaofeng; Liao, Yuan; Alam, Mahabub Maraj; Mathur, Ramkumar; Feustel, Paul J.; Mazurkiewicz, Joseph E.; Adamo, Matthew A.; Zhu, Xingen; Huang, Yunfei

doi:10.1523/jneurosci.2754-19.2020

Cited by 41 publications

(26 citation statements)

References 76 publications

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“…We found that excessive activation of mTOR in TSC1-deficient mice leads to severe spontaneous seizures, involving a noninflammatory mechanism ( Zhao et al, 2018 ). Our recent study revealed that deletion of microglial mTOR increases excitatory neuronal death and spontaneous recurrent seizures ( Zhao et al, 2020 ). Here, we found that deletion of Atg7 in microglia promotes increased amounts of mature ODCs and myelination markers.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Microglial Autophagy Increases the Density of Oligodendrocytes and Susceptibility to Severe Forms of Seizures

Alam

Zhao

Liao

et al. 2021

eNeuro

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Excessive activation of mTOR in microglia impairs CNS homeostasis and causes severe epilepsy. Autophagy constitutes an important part of mTOR signaling. The contribution of microglial autophagy to CNS homeostasis and epilepsy remains to be determined. Here, we report that ATG7KO mice deficient for autophagy in microglia display a marked increase of myelination markers, a higher density of mature oligodendrocytes (ODCs), and altered lengths of the nodes of Ranvier. Moreover, we found that deficiency of microglial autophagy (ATG7KO) leads to increased seizure susceptibility in three seizure models (pilocarpine, kainic acid, and amygdala kindling). We demonstrated that ATG7KO mice develop severe generalized seizures and display nearly 100% mortality to convulsions induced by pilocarpine and kainic acid. In the amygdala kindling model, we observed significant facilitation of contralateral propagation of seizures, a process underlying the development of generalized seizures. Taken together, our results reveal impaired microglial autophagy as a novel mechanism underlying altered homeostasis of ODCs and increased susceptibility to severe and fatal generalized seizures.

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Section: Discussionmentioning

confidence: 99%

Deficiency of Microglial Autophagy Increases the Density of Oligodendrocytes and Susceptibility to Severe Forms of Seizures

Alam

Zhao

Liao

et al. 2021

eNeuro

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“…32 This detrimental effect was further confirmed by two recent studies wherein microglia were depleted in a similar fashion. 33,34 These conflicting reports can be attributed to the heterogeneity of activated microglia that is largely present following an insult. Resting microglia can either transition to the proinflammatory and neurotoxic M 1 phenotype or the anti-inflammatory M 2 phenotype.…”

Section: Epilepsy and Inflammationmentioning

confidence: 99%

Targeting Neuroinflammation via Purinergic P2 Receptors for Disease Modification in Drug-Refractory Epilepsy

Engel¹,

Smith²,

Alves³

2021

JIR

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Treatment of epilepsy remains a clinical challenge, with >30% of patients not responding to current antiseizure drugs (ASDs). Moreover, currently available ASDs are merely symptomatic without altering significantly the progression of the disease. Inflammation is increasingly recognized as playing an important role during the generation of hyperexcitable networks in the brain. Accordingly, the suppression of chronic inflammation has been suggested as a promising therapeutic strategy to prevent epileptogenesis and to treat drug-refractory epilepsy. As a consequence, a strong focus of ongoing research is identification of the mechanisms that contribute to sustained inflammation in the brain during epilepsy and whether these can be targeted. ATP is released in response to several pathological stimuli, including increased neuronal activity within the central nervous system, where it functions as a neuro-and gliotransmitter. Once released, ATP activates purinergic P2 receptors, which are divided into metabotropic P2Y and ionotropic P2X receptors, driving inflammatory processes. Evidence from experimental models and patients demonstrates widespread expression changes of both P2Y and P2X receptors during epilepsy, and critically, drugs targeting both receptor subtypes, in particular the P2Y 1 and P2X 7 subtypes, have been shown to possess both anticonvulsive and antiepileptic potential. This review provides a detailed summary of the current evidence suggesting ATP-gated receptors as novel drug targets for epilepsy and discusses how P2 receptor-driven inflammation may contribute to the generation of seizures and the development of epilepsy.

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“…Interestingly, blockade of microglial proliferation during the chronic disease phase (i.e., starting day 58 until day 71 post-SE) resulted in SRS reduction [266]. Moreover, Zhao et al [267] showed that mTOR-deficient microglia exposed to an excitatory injury in vitro lose their proliferative and inflammatory responses, as well as fail to effectively engulf damaged neurons. Additionally, Alam et al [268] validated that impaired microglial autophagy, which acts downstream of mTOR, leads to increased seizure susceptibility and causes severe seizures.…”

Section: Gliamentioning

confidence: 99%

Sleep Disruption Worsens Seizures: Neuroinflammation as a Potential Mechanistic Link

Bonilla-Jaime

Zeleke

Rojas

et al. 2021

IJMS

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Sleep disturbances, such as insomnia, obstructive sleep apnea, and daytime sleepiness, are common in people diagnosed with epilepsy. These disturbances can be attributed to nocturnal seizures, psychosocial factors, and/or the use of anti-epileptic drugs with sleep-modifying side effects. Epilepsy patients with poor sleep quality have intensified seizure frequency and disease progression compared to their well-rested counterparts. A better understanding of the complex relationship between sleep and epilepsy is needed, since approximately 20% of seizures and more than 90% of sudden unexpected deaths in epilepsy occur during sleep. Emerging studies suggest that neuroinflammation, (e.g., the CNS immune response characterized by the change in expression of inflammatory mediators and glial activation) may be a potential link between sleep deprivation and seizures. Here, we review the mechanisms by which sleep deprivation induces neuroinflammation and propose that neuroinflammation synergizes with seizure activity to worsen neurodegeneration in the epileptic brain. Additionally, we highlight the relevance of sleep interventions, often overlooked by physicians, to manage seizures, prevent epilepsy-related mortality, and improve quality of life.

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Microglial mTOR is Neuronal Protective and Antiepileptogenic in the Pilocarpine Model of Temporal Lobe Epilepsy

Cited by 41 publications

References 76 publications

Deficiency of Microglial Autophagy Increases the Density of Oligodendrocytes and Susceptibility to Severe Forms of Seizures

Deficiency of Microglial Autophagy Increases the Density of Oligodendrocytes and Susceptibility to Severe Forms of Seizures

Targeting Neuroinflammation via Purinergic P2 Receptors for Disease Modification in Drug-Refractory Epilepsy

Sleep Disruption Worsens Seizures: Neuroinflammation as a Potential Mechanistic Link

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