Deficiency of microglial autophagy increases the density of oligodendrocytes and susceptibility to severe forms of seizures

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Abstract

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, 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 oligodendrocytes and increased susceptibility to severe and fatal generalized seizures.

Significance statement Microglia play a critical role in CNS homeostasis, predominantly by impinging on neurons and astrocytes. A role for microglia in the development of oligodendrocytes has begun to be recognized, but the mechanism remains largely unknown. The present study uncovered a novel role of microglial autophagy in oligodendrocyte homeostasis. Importantly, we found that deficiency of microglial autophagy causes severe forms of generalized seizures and high mortality, pointing to a strong association of altered oligodendrocyte homeostasis and epilepsy. Our findings have implications in understanding severe forms of epilepsy.

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