HepaCAM knockdown impairs learning and memory in mice by regulating cholesterol synthesis pathway

Astrocytes engage in metabolic interactions with nearby neurons by supplying various substances. However, how they regulate learning and memory through changes in the metabolic state of neurons is still unclear. In this study, we show that knocking down astrocytic hepaCAM silences genes related to cholesterol biosynthesis in astrocytes, leading to a decrease in cholesterol levels. Additionally, astrocytes play a crucial role in synapse development and function by releasing signals that guide neurons. Consequently, without enough cholesterol, the level of neuronal synaptic proteins and the density of dendritic spines decrease. Then we demonstrate that knocking down hepaCAM leads to impaired learning and memory in mice. Collectively, hepaCAM, a cell adhesion molecules specifically expressed in astrocytes, regulates learning and memory by regulating the cholesterol synthesis pathway. Overall design: To investigate the role of hepaCAM in mouse hippocampus, we knocked down hepaCAM in mouse hippocampus by shRNA. Next, we compared the gene expression profiles of RNA-seq data from the hippocampus of WT and hepaCAM KD mice