EP300-interacting inhibitor of differentiation 1 (Eid1) regulates differentiation, transcription and acetyltransferase activity. But the main function of Eidl in the brain is still unclear. To better understand this issue, we generated Eid1-knockout (Eid1-KO) mice. We found poorer learning and memory ability, and smaller volume of neonatal telencephalon in Eidl-KO group than wild-type (WT). Bioinformatics implied that Eid1 may directly regulate cell proliferation. We then isolated neural stem cells (NSCs) and discovered a slower proliferation rate in Eid1-KO NSC5. Moreover, based on bioinformatics results, we investigated the expression of phosphatidylinositol 3-kinase (PI3K)/AKT/GSK313 pathway by Western blotting assay, which showed attenuated in Eid1-KO group. Our data proved the first comprehensive report of Eid1 regulating NSCs proliferation via PI3K/AKT/GSK313 pathway, and provide a foundation for the role of EID1 in the brain. (C) 2019 Elsevier Inc. All rights reserved.