Nedl1 knockout ameliorates cognitive impairment and improves epilepsy threshold in pilocarpine-induced epileptic mice

TL;DR

Removing the NEDL1 protein in mice reduces seizures and improves memory in a model of epilepsy.

Contribution

This study shows that Nedl1 knockout reduces epilepsy severity and cognitive deficits in mice.

Findings

Nedl1−/− mice showed improved spatial learning and memory in the Barnes maze.

Nedl1 knockout reduced hippocampal damage and microglial activation in epileptic mice.

RNA-seq analysis revealed T-cell-related pathways enriched in Nedl1−/− mice.

Abstract

Epilepsy is a common neurological disorder. The homologous to E6-AP carboxy terminus (HECT) E3 ligase is associated with epilepsy. NEDD4-like ubiquitin protein ligase-1 (NEDL1) is a HECT E3 ligase that is highly expressed in the brain. This study aimed to investigate the involvement of NEDL1 in epilepsy and the potential effect of NEDL1 on the cognitive ability.

The pilocarpine-induced epileptic mouse model was used to assess cognitive functions in Barnes maze, the pathological changes, and the activation of astrocytes and microglia in wild-type (Nedl1+/+) and Nedl1 knockout (Nedl1−/−) mice. The RNA-seq method was used to analyze differentially expressed genes and explore the brain pathophysiology after epilepsy development.

Nedl1 knockout resulted in a protective effect against epilepsy. The Nedl1−/− mice showed improved spatial learning and memory, alleviation of pathological damage in the hippocampus induced by epilepsy, and reduced microglial activation in the hippocampus. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes also revealed several prominently enriched T-cell-related pathways.

Nedl1 knockout reduces seizures and alleviates neuroinflammation. The potential functional link between NEDL1 and epilepsy provides a new approach to the treatment and intervention of epilepsy.

The online version contains supplementary material available at 10.1186/s42494-024-00186-z.

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