Prominent decrease of hippocampal neurogenesis in a spontaneous model of type 1 diabetes (T1D), the nonobese diabetic mice (NOD): a probable link with diabetes associated-depression?

SARAVIA F.; BEAUQUIS J; COULAUD, J.; ROIG, P.; HOMO-DELARCHE, F; DE NICOLA, AF

Copenhague, Dinamarca

Congreso; European Association for the Study of Diabetes; 2006

EASD

Abstract submitted to EASD 2006 Prominent decrease of hippocampal neurogenesis in a spontaneous model of type 1 diabetes (T1D), the nonobese diabetic mice (NOD): a probable link with diabetes associated-depression? Saravia, Flavia; Beauquis, Juan; Coulaud, Josiane; Roig, Paulina; Homo-Delarche, Francoise; De Nicola, Alejandro. Institute of Biology and Experimental Medicine , Department of Biochemistry, Faculty of Medicine, University of Buenos Aires, Argentine and CNRS 7059 Université Paris 7, Paris, France. Background and aims: The production of new neurons (neurogenesis) in the adult brain is restricted to two brain areas, the subventricular zone and the dentate gyrus (DG) of the hippocampus. In the DG, this plastic event is associated to specific types of learning and is especially modulated by hormones, environmental factors (stress, exercise), and aging. Defective neurogenesis is intimately linked to inflammation, affective-related disorders and depression. In human diabetes, degenerative and functional disorders of the central nervous system, including a high incidence of depression, are common findings. We recently reported that DG neurogenesis is reduced in streptozotocin (STZ)-treated mice, a pharmacological model of T1D. Here, we wanted to explore DG neurogenesis before and after diabetes onset in the NOD mouse, a well described spontaneous T1D model. Materials and methods: DG cell proliferation and survival were studied as a function of age in prediabetic and diabetic NOD and control C57BL/6 and BALB/C female mice, using different protocols of 5-bromo-2’-deoxyuridine (BrdU) incorporation, and cell phenotype analysis by immunocytochemical co-detection for glial (GFAP) or neuronal (Neu-N) markers and confocal microscopy. Results: In the first protocol, cell proliferation was assessed in the DG of 4, 8 and 12-week-old control strains and NOD mice (the 12-week-old NOD mice were overtly diabetic, whereas the 4- and 8-week-old groups were pre-diabetic). Levels of BrdU positive cells in NOD DG were, regardless of age, constantly and significantly lower than in controls, showing that hippocampal alterations are present far before diabetes onset in NOD mice. The second protocol was designed to study survival of the newly-generated cells: 15-week-old animals were sacrificed 21 days after BrdU injection. Here, in addition to controls, two subsets of NOD mice were considered: non diabetic (noDb) and diabetic (Db). Cell survival in NOD DG was significantly lower than C57BL/6, where 599.4 ± 78.9 BrdU+ cells were found per DG while the values corresponding to NOD Db were 138.9 ± 27.2 (p<0.001) and NOD noDb, 313.6 ± 41.0 (p<0.01). Moreover, the presence of diabetes strongly aggravated cell survival in DG (p<0.05). However, analysis of cell phenotype assessed by co-localization with glial or neuronal markers and confocal microscopy determined that the proportion of neurons in these groups was not altered by the diabetic state. Conclusion: Like in the pharmacological T1D model, the STZ-treated mouse, hippocampal neurogenesis is strongly diminished in the spontaneous T1D model of the NOD mouse. Notably, in the STZ model, we previously showed that antidepressant treatment (fluoxetine) induced complete recovering of proliferation of cells potentially becoming neurons, an effect that might result from improvement of hypothalamo-pituitary-adrenal axis that is known to be altered in rodent and human diabetes. Here, in addition, we showed that hippocampal DG cell proliferation defect takes place during the prediabetic stage in the NOD mouse. Whether this early alteration might result, in this autoimmune strain, from HPA axis alterations and/or ongoing brain inflammatory process remains to be investigated.