Effects of TRPM7/miR-34a Gene Silencing on Spatial Cognitive Function and Hippocampal Neurogenesis in Mice with Type 1 Diabetes Mellitus.

Abstract

This study aimed to explore the effects of transient receptor potential melastatin 7 (TRPM7)/microRNA-34a (miR-34a) gene silencing on spatial cognitive function and hippocampal neurogenesis in mice with type 1 diabetes mellitus (T1DM). BALB/c mice were chosen to establish T1DM models and divided into five groups respectively: the negative control (NC), T1DM, T1DM+si-TRPM7, T1DM+si-miR-34a, and T1DM+si-TRPM7+si-miR-34a groups. Morris water maze (MWM) test was adopted to observe behavioral alterations in mice. In all groups, changes in weight, fasting insulin, blood glucose, and insulin-related antibodies: insulin autoantibody (IAA), islet cell antibody (ICA), and glutamic acid decarboxylase antibody (GAD-Ab) were monitored. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to test TRPM7 and miR-34a expressions. Nissl staining was performed to detect neuron numbers in hippocampal tissues. Ultrastructure of hippocampal neurons was observed by transmission electron microscopy. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to assess cell apoptosis, and Western blotting was applied to examine expressions of apoptosis-related proteins. Compared to the NC group, the mice in the T1DM group had increased expressions of TRPM7 and miR-34a; decreased weight and fasting insulin; increased blood glucose and levels of ICA, IAA, and GAD-Ab; prolonged escape latency; less time spent in the target quadrant; incomplete neuronal structure; reduced neuron numbers; increased cell apoptosis and expressions of activated Bax, Cyt-c, and cleaved caspase-3; but reduced Bcl-2 expression. In comparison to the T1DM group, the T1DM+si-TRPM7, T1DM+si-miR-34a, and T1DM+si-TRPM7+si-miR-34a groups showed increased weight and fasting insulin; reduced blood glucose and levels of ICA, IAA, and GAD-Ab; shortened escape latency; prolonged time spent in the target quadrant platform; intact neuronal structure; increased neuron numbers; repaired neurons; reduced cell apoptosis and expressions of activated Bax, Cyt-c, and cleaved caspase-3; but increased Bcl-2 expression. The T1DM+si-TRPM7+si-miR-34a group underwent more obvious changes than the T1DM+si-TRPM7 and T1DM+si-miR-34a groups. Our results demonstrated that TRPM7/miR-34a gene silencing could improve spatial cognitive function and protect hippocampal neurogenesis in mice with T1DM.