title: Chronic cortisol exposure promotes the development of a GABAergic phenotype in the primate hippocampus.
abstract: Glucocorticoids regulate plasticity and survival of hippocampal neurons. Aberrant exposure to this steroid hormone can result in neurodegeneration, perhaps secondary to disruption of calcium homeostasis. Calbindin, a calcium-binding protein that buffers excess calcium, may protect against neurodegeneration resulting from overabundance of intracellular calcium. In this study, we examined whether chronic treatment (1 year) with cortisol enhances hippocampal calbindin expression in primates. Calbindin is a marker for inhibitory neurons and the dentate gyrus is known to adopt an inhibitory phenotype in response to extreme conditions such as seizures. Thus, we hypothesized that chronic cortisol exposure may also promote a GABAergic phenotype. Therefore, we examined the expression of the GABA-synthesizing enzyme glutamic acid decarboxylase. The expression of brain-derived neurotrophic factor, which is responsive to glucocorticoids, was also examined. Our results demonstrate significant increases in calbindin, glutamic acid decarboxylase and brain-derived neurotrophic factor in several regions of the primate hippocampus, including the dentate gyrus and CA3, in response to chronic cortisol exposure. These results suggest that chronic cortisol exposure may shift the balance towards a GABAergic phenotype, perhaps as part of a compensatory feedback mechanism to dampen the initial excitatory effects of glucocorticoids in the hippocampus.
authors.affiliation: Department of Psychiatry, University of Washington School of Medicine, Seattle, Washington, USA. pammcm@u.washington.edu
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McMillan
authors.forename: Charles W
authors.initials: CW
authors.lastname: Wilkinson
authors.forename: Lynne
authors.initials: L
authors.lastname: Greenup
authors.forename: Murray A
authors.initials: MA
authors.lastname: Raskind
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Peskind
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D064032:Calbindin 2; D064026:Calbindins; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D006854:Hydrocortisone / Q000494:pharmacology*; D008254:Macaca nemestrina; D008297:Male; D010320:Parvalbumins / Q000096:biosynthesis; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013995:Time; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D064032:Calbindin 2; D064026:Calbindins; D010320:Parvalbumins; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; D006854:Hydrocortisone