title: Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder.
abstract: Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10-13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD.
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; Department of Psychiatry, New York University Medical Center, New York, NY, USA. Electronic address: smiley@nki.rfmh.org.
authors.forename: John F
authors.initials: JF
authors.lastname: Smiley
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; Department of Psychiatry, New York University Medical Center, New York, NY, USA.
authors.forename: Mariko
authors.initials: M
authors.lastname: Saito
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bleiwas
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Masiello
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Ardekani
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Guilfoyle
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Gerum
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; Department of Child and Adolescent Psychiatry, New York University Medical Center, New York, NY, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Wilson
authors.affiliation: Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; Department of Psychiatry, New York University Medical Center, New York, NY, USA.
authors.forename: Csaba
authors.initials: C
authors.lastname: Vadasz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000473:pathology*; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000473:pathology*; D059330:GABAergic Neurons / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009929:Organ Size; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology*
chemical_list: D000431:Ethanol
keywords: Cortex thickness; Fetal alcohol; Gender difference; Interneuron; Neocortex; Stereology