title: Pre-conditioning induces the precocious differentiation of neonatal astrocytes to enhance their neuroprotective properties.
abstract: Hypoxic preconditioning reprogrammes the brain's response to subsequent H/I (hypoxia-ischaemia) injury by enhancing neuroprotective mechanisms. Given that astrocytes normally support neuronal survival and function, the purpose of the present study was to test the hypothesis that a hypoxic preconditioning stimulus would activate an adaptive astrocytic response. We analysed several functional parameters 24 h after exposing rat pups to 3 h of systemic hypoxia (8% O2). Hypoxia increased neocortical astrocyte maturation as evidenced by the loss of GFAP (glial fibrillary acidic protein)-positive cells with radial morphologies and the acquisition of multipolar GFAP-positive cells. Interestingly, many of these astrocytes had nuclear S100B. Accompanying their differentiation, there was increased expression of GFAP, GS (glutamine synthetase), EAAT-1 (excitatory amino acid transporter-1; also known as GLAST), MCT-1 (monocarboxylate transporter-1) and ceruloplasmin. A subsequent H/I insult did not result in any further astrocyte activation. Some responses were cell autonomous, as levels of GS and MCT-1 increased subsequent to hypoxia in cultured forebrain astrocytes. In contrast, the expression of GFAP, GLAST and ceruloplasmin remained unaltered. Additional experiments utilized astrocytes exposed to exogenous dbcAMP (dibutyryl-cAMP), which mimicked several aspects of the preconditioning response, to determine whether activated astrocytes could protect neurons from subsequent excitotoxic injury. dbcAMP treatment increased GS and glutamate transporter expression and function, and as hypothesized, protected neurons from glutamate excitotoxicity. Taken altogether, these results indicate that a preconditioning stimulus causes the precocious differentiation of astrocytes and increases the acquisition of multiple astrocytic functions that will contribute to the neuroprotection conferred by a sublethal preconditioning stress.
authors: Department of Neurology and Neurosciences, UMDNJNew Jersey Medical School, Newark, NJ 07103, U.S.A.
authors: Ellora
authors: E
authors: Sen
authors: Anirban
authors: A
authors: Basu
authors: Lisa B
authors: LB
authors: Willing
authors: Tracy F
authors: TF
authors: Uliasz
authors: Jaimie L
authors: JL
authors: Myrkalo
authors: Susan J
authors: SJ
authors: Vannucci
authors: Sandra J
authors: SJ
authors: Hewett
authors: Steven W
authors: SW
authors: Levison
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D019194:Ischemic Preconditioning; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018696:Neuroprotective Agents; D051381:Rats; D017208:Rats, Wistar
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; C493392:Slc1a3 protein, rat; D018698:Glutamic Acid; D005974:Glutamate-Ammonia Ligase