Multiple effects of mitochondrial division inhibitor mdivi-1 on granular neurons of the dentate gyrus in rats

Introduction. Inhibitors of mitochondrial fission are considered promising pharmacological agents with neuroprotective effects; however, their effects on neurogenic niches have not been sufficiently characterized. The aim was to employ morphological methods to characterize the effect of mdivi-1 (mitochondrial division inhibitor) on neurons of the granular layer of the dentate gyrus and neurogenesis in the subgranular zone. Materials and methods. Twenty 4-month male Wistar rats had intracerebroventricular and intraperitoneal mdivi-1 administration.Immunomorphological methods were used to evaluate changes in differentiation and proliferation of neuronal precursors, the level of immunostaining for synaptic proteins, and mitochondrial changes in detecting proteins of respiratory complexes I, II, and V. Moreover, we evaluated the effect of mdivi-1 on behavioral performance of animals in “the open field” and “T-maze” tests. Results. Intraventricular and intraperitoneal mdivi-1 administration decreased the density of doublecortin-positive neuronal precursors, suppressed dendrite development, and reduced the number of BrdU-labeled neurons in the dentate gyrus. Suppression of neurogenesis was accompanied by changes in immunostaining for the synaptic proteins synaptophysin and PSD95, an increase in the mitochondrial size in neurons of granular layer, and changes in animal behavior. We also detected a decrease in immunostaining for ATP5H subunit of ATP synthase. These changes were observed 14 days after mdivi-1 administration. The inhibitor mdivi-1 is supposed to directly affect synapses. The identified synaptic structural changes are likely to be caused by the resulting inhibition of neurogenesis in the dentate gyrus. Conclusion. The mitochondrial division inhibitor mdivi-1 suppresses neurogenesis in the dentate gyrus and causes changes in the level of immunostaining of synaptic proteins. The observed effects of mdivi-1 demonstrate the role of mitochondrial fission in neuronal development and should be accounted for when considering mdivi-1 and similar Drp1 inhibitors as potential pharmacologic agents in treating neurological diseases. Keywords: mitochondrial fission, Drp1, mdivi-1, hippocampus, neurogenesis