Contribution of neural cell death to depressive phenotypes of streptozotocin-induced diabetic mice

Abstract

Abstract Major depression disorder (MDD) or depression is highly prevalent in diabetic patients, where the depressive symptoms are more severe and less responsive to antidepressant therapies. The underlying mechanism is little understood. We hypothesized that the pathophysiology of comorbid depression was more complex than that proposed for MDD and that neural cell death played a role in the disease severity. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic mice. These mice had blood glucose 3 fold above controls and exhibited depressive phenotypes as judged by a battery of behavioral tests, thus confirming the comorbidity in mice. Immunohistological studies showed markedly increased TUNEL positive cells in the frontal cortex and hippocampus of the comorbid mice. The apoptosis were supported by increased caspase-3 and decreased Bcl-2 proteins in the brain regions. In addition, the serum BDNF level of comorbid mice was reduced, further supporting the neurodenerative change. Mechanistic analyses showed an increased expression of mitochondrial fission genes fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1) and a decreased expression of mitochondrial fusion genes mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optical atrophy 1 (Opa1). Representative assessment of proteins Drp1 and Mfn2 mirrored the mRNA changes. The data demonstrated that neural cell death was associated with the depressive phenotype of comorbid mice and that a fission-dominant expression of genes and proteins mediating mitochondrial dynamics played a role in the hyperglycemia-induced cell death. The study provides new insight into the disease mechanism and may lend evidence of developing novel therapeutics aiming at neuroprotection by modulating mitochondrial dynamics to treat comorbid depression with diabetes.