PMID- 24764190 OWN - NLM STAT- MEDLINE DCOM- 20150112 LR - 20211021 IS - 1754-8411 (Electronic) IS - 1754-8403 (Print) IS - 1754-8403 (Linking) VI - 7 IP - 6 DP - 2014 Jun TI - Contribution of neural cell death to depressive phenotypes of streptozotocin-induced diabetic mice. PG - 723-30 LID - 10.1242/dmm.016162 [doi] AB - Major depression disorder (MDD) or depression is highly prevalent in individuals with diabetes, and the depressive symptoms are more severe and less responsive to antidepressant therapies in these patients. 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 levels threefold 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, indicating apoptosis. This finding was supported by increased caspase-3 and decreased Bcl-2 proteins in these brain regions. In addition, the serum brain-derived neurotrophic factor (BDNF) level of comorbid mice was reduced compared with controls, further supporting the neurodegenerative 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 the 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 could aid the development of novel therapeutics aimed at providing neuroprotection by modulating mitochondrial dynamics to treat comorbid depression with diabetes. CI - (c) 2014. Published by The Company of Biologists Ltd. FAU - Chen, Cheng AU - Chen C AD - Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China. FAU - Wang, Yun AU - Wang Y AD - Department of Molecular Pathology, Shantou University Medical College, Shantou 515041, China. FAU - Zhang, Juan AU - Zhang J AD - Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China. FAU - Ma, Lian AU - Ma L AD - Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China. Laboratory of Translational Medicine, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China. FAU - Gu, Jiang AU - Gu J AD - Department of Molecular Pathology, Shantou University Medical College, Shantou 515041, China. Laboratory of Translational Medicine, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China. FAU - Ho, Guyu AU - Ho G AD - Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China. Laboratory of Translational Medicine, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China. guyu.ho@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140424 PL - England TA - Dis Model Mech JT - Disease models & mechanisms JID - 101483332 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 5W494URQ81 (Streptozocin) SB - IM MH - Animals MH - Apoptosis MH - Behavior, Animal MH - Brain-Derived Neurotrophic Factor/metabolism MH - *Cell Death MH - Depressive Disorder, Major/*complications MH - Diabetes Mellitus, Experimental/complications/*pathology MH - Frontal Lobe/pathology MH - Hippocampus/pathology MH - In Situ Nick-End Labeling MH - Mice MH - Neurons/*cytology MH - Streptozocin PMC - PMC4036479 OTO - NOTNLM OT - Apoptosis OT - Comorbidity OT - Depression OT - Diabetes OT - Mitochondria OT - Neurodegeneration EDAT- 2014/04/26 06:00 MHDA- 2015/01/13 06:00 PMCR- 2014/06/01 CRDT- 2014/04/26 06:00 PHST- 2014/04/26 06:00 [entrez] PHST- 2014/04/26 06:00 [pubmed] PHST- 2015/01/13 06:00 [medline] PHST- 2014/06/01 00:00 [pmc-release] AID - dmm.016162 [pii] AID - 0070723 [pii] AID - 10.1242/dmm.016162 [doi] PST - ppublish SO - Dis Model Mech. 2014 Jun;7(6):723-30. doi: 10.1242/dmm.016162. Epub 2014 Apr 24.