Targeting enhancing myelin regeneration reverses cognitive deficits in a mouse model of intellectual disability.

The early postnatal period is a critical window for brain maturation, during which oligodendrogenesis, myelination, and synaptogenesis are dynamically orchestrated to support cognitive development. Clinical studies have associated myelination deficits with intellectual disability (ID), but the molecular mechanisms linking myelin deficits to cognitive dysfunction remain poorly understood. Here, we generated an inducible conditional knockout (icKO) mouse model to selectively ablate 3-phosphoinositide-dependent protein kinase-1 (PDK1) in oligodendrocyte precursor cells (OPCs) during early postnatal development. Pdk1 icKO mice exhibited severe deficits in hippocampal oligodendrocyte (OL) maturation, myelination, and excitatory synaptogenesis, accompanied by impaired neuronal activation and profound memory impairments. Mechanistically, PDK1 loss led to suppression of the Akt-mTOR signaling pathway, a critical regulator of OL differentiation and myelination. Strikingly, treatment with clemastine, an FDA-approved pro-myelinating agent, effectively restored oligodendrogenesis, myelination, synaptic integrity, neuronal activity, and cognitive performance in Pdk1 icKO mice, in part by reactivating Akt-mTOR signaling. Together, these findings identify PDK1 as a pivotal regulator of postnatal myelination and cognitive maturation, establish a mechanistic link between oligodendroglial dysfunction and ID, and highlight clemastine as a promising therapeutic candidate for cognitive disorders associated with myelination deficits.