Peri-pubertal maturation after developmental disturbance: a model for psychosis onset in the rat.
Schizophrenia is thought to be associated with abnormalities during neurodevelopment although those disturbances usually remain silent until puberty; suggesting that postnatal brain maturation precipitates the emergence of psychosis. In an attempt to model neurodevelopmental defects in the rat, brain cellular proliferation was briefly interrupted with methylazoxymethanol (MAM) during late gestation at embryonic day 17 (E17). The litters were explored at pre- and post-puberty and compared with E17 saline-injected rats. We measured spontaneous and provoked locomotion, working memory test, social interaction, and prepulse inhibition (PPI). As compared with the saline-exposed rats, the E17 MAM-exposed rats exhibited spontaneous hyperactivity that emerged only after puberty. At adulthood, they also exhibited hypersensitivity to the locomotor activating effects of a mild stress and a glutamatergic N-methyl-D-aspartate receptor antagonist (MK-801), as well as PPI deficits whereas before puberty no perturbations were observed. In addition, spatial working memory did not undergo the normal peri-pubertal maturation seen in the sham rats. Social interaction deficits were observed in MAM rats, at both pre- and post-puberty. Our study further confirms that transient prenatal disruption of neurogenesis by MAM at E17 is a valid behavioral model for schizophrenia as it is able to reproduce some fundamental features of schizophrenia with respect to both phenomenology and temporal pattern of the onset of symptoms and deficits.
Le Pen
G
G
INSERM, U796, Pathophysiology of Psychiatric Disorders, University Paris Descartes, Sainte-Anne Hospital, Centre Paul Broca, Paris F-75014 France. lepen@broca.inserm.fr
Gourevitch
R
R
Hazane
F
F
Hoareau
C
C
Jay
T M
TM
Krebs
M-O
MO
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000254:growth & development*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D007266:Inhibition, Psychological; D007398:Interpersonal Relations; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011618:Psychotic Disorders / Q000209:etiology / Q000503:physiopathology*; D051381:Rats; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D008746:Methylazoxymethanol Acetate; D016291:Dizocilpine Maleate; C030667:methylazoxymethanol