CNS Synaptogenesis Promoted by Glia-Derived Cholesterol

TLDR

Synaptogenesis in the CNS is poorly understood, yet glia‑derived factors promote synapse development, and neurons require additional cholesterol from glia to form mature synapses. The study identifies the glia‑derived factor that promotes synaptogenesis as cholesterol complexed to apolipoprotein E–containing lipoproteins. Cholesterol availability limits synapse development, explaining the delayed onset of CNS synaptogenesis after glial differentiation and neurobehavioral deficits associated with cholesterol or lipoprotein disorders.

Abstract

The molecular mechanisms controlling synaptogenesis in the central nervous system (CNS) are poorly understood. Previous reports showed that a glia-derived factor strongly promotes synapse development in cultures of purified CNS neurons. Here, we identify this factor as cholesterol complexed to apolipoprotein E–containing lipoproteins. CNS neurons produce enough cholesterol to survive and grow, but the formation of numerous mature synapses demands additional amounts that must be provided by glia. Thus, the availability of cholesterol appears to limit synapse development. This may explain the delayed onset of CNS synaptogenesis after glia differentiation and neurobehavioral manifestations of defects in cholesterol or lipoprotein homeostasis.