Type 2 diabetic (T2D) patients often develop early cognitive and sensorimotor impairments. The pathophysiological mechanisms behind these problems are largely unknown. Recent studies demonstrate that dysfunctional γ-Aminobutyric acid (GABAergic) neurons are involved in age-related cognitive decline. We hypothesized that similar, but earlier dysfunction is taking place under T2D in the neocortex and striatum (two brain areas important for cognition and sensorimotor functions). We also hypothesized that the T2D-induced effects are pharmacologically reversible by anti-diabetic drugs targeting the glucagon-like peptide-1 receptor (GLP-1R).
We determined the effect of T2D on cortical and striatal GABAergic neurons positive for GAD67, Calbindin, Parvalbumin and Calretinin by using immunohistochemistry and quantitative microscopy. Young and middle-aged T2D Goto-Kakizaki (GK) (a model of spontaneous T2D) and Wistar rats were used. Furthermore, we determined the therapeutic potential of the GLP1-R agonist exendin-4 by treating middle-aged GK rats for six weeks with 0.1 µg/kg exendin-4 twice daily.
We show that T2D reduced the density of GAD67-positive neurons in the striatum and of Calbindin-positive neurons in both striatum and neocortex. T2D also increased the average volume of Parvalbumin-positive interneurons in the striatum. Exendin-4 treatment increased the density of Calbindin-positive neurons in the striatum of GK rats.
Our data demonstrate that T2D negatively affects GAD67 and Calbindin-positive GABAergic neurons in the brain during aging, potentially identifying some of the pathophysiological mechanisms to explain the increased prevalence of neurological complications in T2D. We also show a specific, positive effect of Exendin-4 on striatal Calbindin-positive neurons, which could be exploited in therapeutic perspective.
- neurological disorders
- glucagon-like peptide-1
- ©2016 The Author(s)
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