Impaired neural stem/progenitor cell proliferation in streptozotocin-induced and spontaneous diabetic mice

Abstract

Diabetes mellitus is associated with adverse complications in many organ systems including the brain. Accumulating evidence indicates that diabetes, regardless of its type, impairs adult neurogenesis in the dentate gyrus (DG) of the hippocampus (HPC). However, the effects of the disease on neurogenesis in the subventricular zone (SVZ) are not well established. We induced diabetes in male NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mice and C57BL/6 mice with a single intraperitoneal injection of streptozotocin (STZ). On day 7 or day 21 after STZ injection mice received the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) for labeling of proliferative cells. Mice were sacrificed 24h later and brain coronal sections were stained with anti-BrdU antibodies. Neural stem/progenitor cell (NSC/NPC) proliferation, as revealed by BrdU-labeled cells, was markedly decreased in the subgranular zone of the DG in STZ-treated diabetic mice. A similar reduction of NSC/NPC proliferation was seen in the SVZ. Reduced DG and SVZ cell proliferation was also found in diabetic NOD mice, a model of spontaneous diabetes, and the reduction was attenuated by bilateral adrenalectomy (Adx). Adx did not alter blood glucose or insulin levels in either prediabetic or diabetic NOD mice, but Adx partly increased mRNA levels of hippocampal and SVZ brain-derived neurotrophic factor (BDNF), a crucial regulator of NSC/NPC proliferation. Moreover, NOD and NOD/SCID mice showed a more rapid reduction of NSC/NPC proliferation than C57BL/6 mice in response to diabetes. Thus, we conclude that diabetes inhibits cell proliferation in both the SVZ and HPC, and inhibition was associated with elevated glucocorticoid levels and reduced BDNF expression.