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Reduction in the Number of Astrocytes and Their Projections Is Associated with Increased Synaptic Protein Density in the Hypothalamus of Poorly Controlled Diabetic Rats

Department of Endocrinology (A.M.L.-S., A.I.A., L.M.F., A.D.-R.d.C., J.A., J.A.C.), Hospital Infantil Universitario Niño Jesús, and Department of Pediatrics (L.M.F., C.G.-C., A.D.-R.d.C., J.A.), Universidad Autónoma de Madrid, 28009 Madrid, Spain

Address all correspondence and requests for reprints to: Dr. Julie A. Chowen, Hospital Infantil Universitario Niño Jesús, Departamento de Endocrinología, Avenida Menéndez Pelayo, 65, 28009 Madrid, Spain. E-mail: jachowen{at}telefonica.net.

Processes under hypothalamic control, such as thermogenesis, feeding behavior, and pituitary hormone secretion, are disrupted in poorly controlled diabetes, but the underlying mechanisms are poorly understood. Because glial cells regulate neurosecretory neurons through modulation of synaptic inputs and function, we investigated the changes in hypothalamic glia in rats with streptozotocin-induced diabetes mellitus. Hypothalamic glial fibrillary acidic protein (GFAP) levels decreased significantly 6 wk after diabetes onset. This was coincident with decreased GFAP immunoreactive surface area, astrocyte number, and the extension of GFAP immunoreactive processes/astrocyte in the arcuate nucleus. Cell death, analyzed by terminal deoxyuridine 5-triphosphate nick-end labeling and ELISA, increased significantly at 4 wk of diabetes. Proliferation, measured by Western blot for proliferating cell nuclear antigen and immunostaining for phosphorylated histone H-3, decreased in the hypothalamus of diabetic rats throughout the study, becoming significantly reduced by 8 wk. Both proliferation and death affected astroctyes because both phosphorylated histone H-3- and terminal deoxyuridine 5-triphosphate nick-end labeling-labeled cells were GFAP positive. Western blot analysis revealed that postsynaptic density protein 95 and the presynaptic proteins synapsin I and synaptotagmin increased significantly at 8 wk of diabetes, suggesting increased hypothalamic synaptic density. Thus, in poorly controlled diabetic rats, there is a decrease in the number of hypothalamic astrocytes that is correlated with modifications in synaptic proteins and possibly synaptic inputs. These morphological changes in the arcuate nucleus could be involved in neurosecretory and metabolic changes seen in diabetic animals.