title: Diabetes negatively affects cortical and striatal GABAergic neurons: an effect that is partially counteracted by exendin-4.
abstract: 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 glutamic acid decarboxylase-67 (GAD67), calbindin (CB), parvalbumin (PV) and calretinin (CR) 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 (Ex-4) by treating middle-aged GK rats for 6 weeks with 0.1 μg/kg Ex-4 twice daily. We show that T2D reduced the density of GAD67-positive neurons in the striatum and of CB-positive neurons in both striatum and neocortex. T2D also increased the average volume of PV-positive interneurons in the striatum. Ex-4 treatment increased the density of CB-positive neurons in the striatum of GK rats. Our data demonstrate that T2D negatively affects GAD67 and CB-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 Ex-4 on striatal CB-positive neurons, which could be exploited in therapeutic perspective.
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden martin.larsson@sodersjukhuset.se cesare.patrone@ki.se vladimer.darsalia@ki.se.
authors: Martin
authors: M
authors: Larsson
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden.|Department of Anatomy and Neurobiology, Medical University of Gdansk, 80 221 Gdansk, Poland.
authors: Grazyna
authors: G
authors: Lietzau
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden.
authors: David
authors: D
authors: Nathanson
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors: Claes-Göran
authors: CG
authors: Östenson
authors: Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors: Carina
authors: C
authors: Mallard
authors: Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors: Maria E
authors: ME
authors: Johansson
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden.
authors: Thomas
authors: T
authors: Nyström
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden martin.larsson@sodersjukhuset.se cesare.patrone@ki.se vladimer.darsalia@ki.se.
authors: Cesare
authors: C
authors: Patrone
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, 118 83 Stockholm, Sweden martin.larsson@sodersjukhuset.se cesare.patrone@ki.se vladimer.darsalia@ki.se.
authors: Vladimer
authors: V
authors: Darsalia
mesh_terms: D000818:Animals; D064032:Calbindin 2 / Q000378:metabolism; D064026:Calbindins / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D000077270:Exenatide; D059330:GABAergic Neurons / Q000378:metabolism* / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D019579:Neocortex / Q000378:metabolism / Q000503:physiopathology; D010320:Parvalbumins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014688:Venoms / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D064032:Calbindin 2; D064026:Calbindins; D000067757:Glucagon-Like Peptide-1 Receptor; D010320:Parvalbumins; D010455:Peptides; D014688:Venoms; D005680:gamma-Aminobutyric Acid; D000077270:Exenatide; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: diabetes; exendin-4; glucagon-like peptide-1 receptor (GLP-1R); interneurons; neurological complications; γ-aminobutyric acid (GABA)