NTPDase2 suppresses hippocampal astrocyte-supplied cholesterol through hydrolyzing eATP in depression

Depression is associated with cholesterol metabolism dysregulation, but the exact correlation and underlying mechanism remain unclear. Here, our finding reveals a notable reduction in cholesterol, specifically in apolipoprotein E lipoprotein (ApoE-Lps)-carried cholesterol, in cerebrospinal fluid (CSF) of depressed rats exposing to chronic unpredictable mild stress (CUMS) or stress-level corticosterone. Consistently, Mendelian randomization (MR) analysis also showed that low level of total cholesterol in CSF may be as a risk factor associated with the characteristic symptom of depression such as anhedonia. More importantly, intracerebroventricular cholesterol administration alleviates changes in hippocampal neuronal morphology and depressive-like behaviors in CUMS rats. In astrocyte-neuron co-culture in vitro, astrocytic cholesterol release is decreased under corticosterone exposure. Mechanistically, increased nucleoside triphosphate diphosphohydrolase-2 (NTPDase2) suppresses ATP-binding cassette G1 (ABCG1)-mediated cholesterol efflux by hydrolyzing extracellular ATP (eATP) in corticosterone-exposed astrocytes. Knockdown of Ntpdase2 in rat hippocampal astrocytes via adeno-associated virus (AAV) exhibits beneficial effects in increasing hippocampal neuronal cholesterol level, protecting neuronal morphology and improving depressive-like behaviors compared with vehicle-injected corticosterone model. Collectively, this study suggests impaired astrocytic cholesterol efflux as a cause of abnormality in hippocampal neuronal structure and identifies NTPDase2 as a potential therapeutic target for depression.