title: Altered spatial learning, cortical plasticity and hippocampal anatomy in a neurodevelopmental model of schizophrenia-related endophenotypes.
abstract: Adult rats exposed to the DNA-methylating agent methylazoxymethanol on embryonic day 17 show a pattern of neurobiological deficits that model some of the neuropathological and behavioral changes observed in schizophrenia. Although it is generally assumed that these changes reflect targeted disruption of embryonic neurogenesis, it is unknown whether these effects generalise to other antimitotic agents administered at different stages of development. In the present study, neurochemical, behavioral and electrophysiological techniques were used to determine whether exposure to the antimitotic agent Ara-C later in development recapitulates some of the changes observed in methylazoxymethanol (MAM)-treated animals and in patients with schizophrenia. Male rats exposed to Ara-C (30 mg/kg/day) at embryonic days 19.5 and 20.5 show reduced cell numbers and heterotopias in hippocampal CA1 and CA2/3 regions, respectively, as well as cell loss in the superficial layers of the pre- and infralimbic cortex. Birth date labeling with bromodeoxyuridine reveals that the cytoarchitectural changes in CA2/3 are a consequence rather that a direct result of disrupted cortical neurogenesis. Ara-C-treated rats possess elevated levels of cortical dopamine and DOPAC (3,4-didyhydroxypheylacetic acid) but no change in norepinephrine or serotonin. Ara-C-treated rats are impaired in their ability to learn the Morris water maze task and showed diminished synaptic plasticity in the hippocampocortical pathway. These data indicate that disruption of neurogenesis at embryonic days 19.5 and 20.5 constitutes a useful model for the comparative study of deficits observed in other gestational models and their relationship to cognitive changes observed in schizophrenia.
authors: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors: P Leon
authors: PL
authors: Brown
authors: Paul D
authors: PD
authors: Shepard
authors: Greg I
authors: GI
authors: Elmer
authors: Sara
authors: S
authors: Stockman
authors: Rebecca
authors: R
authors: McFarland
authors: Cheryl L
authors: CL
authors: Mayo
authors: Jean Lud
authors: JL
authors: Cadet
authors: Irina N
authors: IN
authors: Krasnova
authors: Martin
authors: M
authors: Greenwald
authors: Carrie
authors: C
authors: Schoonover
authors: Michael W
authors: MW
authors: Vogel
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003561:Cytarabine; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D058068:Endophenotypes; D006624:Hippocampus / Q000196:embryology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012701:Serotonin / Q000378:metabolism
chemical_list: D003561:Cytarabine; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine