title: Transient activation of microglia following acute alcohol exposure in developing mouse neocortex is primarily driven by BAX-dependent neurodegeneration.
abstract: Fetal alcohol exposure is the most common known cause of preventable mental retardation, yet we know little about how microglia respond to, or are affected by, alcohol in the developing brain in vivo. Using an acute (single day) model of moderate (3 g/kg) to severe (5 g/kg) alcohol exposure in postnatal day (P) 7 or P8 mice, we found that alcohol-induced neuroapoptosis in the neocortex is closely correlated in space and time with the appearance of activated microglia near dead cells. The timing and molecular pattern of microglial activation varied with the level of cell death. Although microglia rapidly mobilized to contact and engulf late-stage apoptotic neurons, apoptotic bodies temporarily accumulated in neocortex, suggesting that in severe cases of alcohol toxicity the neurodegeneration rate exceeds the clearance capacity of endogenous microglia. Nevertheless, most dead cells were cleared and microglia began to deactivate within 1-2 days of the initial insult. Coincident with microglial activation and deactivation, there was a transient increase in expression of pro-inflammatory factors, TNFα and IL-1β, after severe (5 g/kg) but not moderate (3 g/kg) EtOH levels. Alcohol-induced microglial activation and pro-inflammatory factor expression were largely abolished in BAX null mice lacking neuroapoptosis, indicating that microglial activation is primarily triggered by apoptosis rather than the alcohol. Therefore, acute alcohol exposure in the developing neocortex causes transient microglial activation and mobilization, promoting clearance of dead cells and tissue recovery. Moreover, cortical microglia show a remarkable capacity to rapidly deactivate following even severe neurodegenerative insults in the developing brain.
authors: Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, Iowa.
authors: Katelin E
authors: KE
authors: Ahlers
authors: Division of Child Neurology, Department of Pediatrics, University of Iowa, Iowa City, Iowa.
authors: Bahri
authors: B
authors: Karaçay
authors: Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, Iowa.
authors: Leah
authors: L
authors: Fuller
authors: Division of Child Neurology, Department of Pediatrics, University of Iowa, Iowa City, Iowa.|Department of Neurology, the Roy J. Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors: Daniel J
authors: DJ
authors: Bonthius
authors: Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, Iowa.
authors: Michael E
authors: ME
authors: Dailey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018821:CD18 Antigens / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D019579:Neocortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018821:CD18 Antigens; D000073883:CX3C Chemokine Receptor 1; D002492:Central Nervous System Depressants; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; C548577:P2ry12 protein, mouse; D010455:Peptides; D019707:Receptors, Chemokine; D058925:Receptors, Purinergic P2Y12; D051028:bcl-2-Associated X Protein; C561617:preimplantation factor, mouse; D000431:Ethanol; D053148:Caspase 3
keywords: apoptosis; development; fetal alcohol spectrum disorders; phagocytosis