# Hippocampal Oligodendrocytes Regulate Mossy Fiber Development Involved in Epileptic Responses

## TL;DR

This study shows that immature brain cells called oligodendrocytes in the hippocampus can lead to epilepsy and that improving their development can reduce seizure risk.

## Contribution

The study reveals a novel role of hippocampal oligodendrocyte differentiation in regulating mossy fiber development and epilepsy susceptibility.

## Key findings

- OL maturation deficiency in Myrf-CKO mice causes spontaneous epilepsy and death.
- Reduced OL differentiation in the hippocampus correlates with impaired mossy fiber development and increased epilepsy risk.
- Treatment with clemastine rescues defective mossy fiber development and reduces adult epilepsy susceptibility.

## Abstract

Although oligodendrocytes (OLs) are known to form the myelin sheath around neuronal axons for the saltatory conduction of action potentials, recent studies have suggested that OLs also modulate neuronal function and plasticity. In the present study, we found that OL maturation deficiency in Myrf-CKO mice caused spontaneous epileptogenesis and resulted in death. To further investigate the association between OL development and epilepsy, we examined the Adamts4 KO mouse line, which has a mild OL differentiation phenotype in the hippocampus. As a result, the differentiation defect in the mutant hippocampus reduced the expression of myelin-associated glycoprotein and lessened its inhibition of the dephosphorylation of phosphorylated tropomyosin-related kinase B, which is associated with retarded adolescent hippocampal mossy fiber development and higher susceptibility to epileptogenesis in adulthood. More importantly, enhancing differentiation by orally administered clemastine rescues the defective mossy fiber development in the early postnatal period and attenuates epilepsy susceptibility in adults. Together, these results strongly suggest that an OL differentiation defect in the hippocampus may contribute to susceptibility to epilepsy in adults.

The online version contains supplementary material available at 10.1007/s12264-025-01452-x.