title: Embryonic and early postnatal abnormalities contributing to the development of hippocampal malformations in a rodent model of dysplasia.
abstract: While there are many recent examples of single gene deletions that lead to defects in cortical development, most human cases of cortical disorganization can be attributed to a combination of environmental and genetic factors. Elucidating the cellular or developmental basis of teratogenic exposures in experimental animals is an important approach to understanding how environmental insults at particular developmental junctures can lead to complex brain malformations. Rats with prenatal exposure to methylazoxymethanol (MAM) reproduce many anatomical features seen in epilepsy patients. Previous studies have shown that heterotopic clusters of neocortically derived neurons exhibit hyperexcitable firing activity and may be a source of heightened seizure susceptibility; however, the events that lead to the formation of these abnormal cell clusters is unclear. Here we used a panel of molecular markers and birthdating studies to show that in MAM-exposed rats the abnormal cell clusters (heterotopia) first appear postnatally in the hippocampus (P1-2) and that their appearance is preceded by a distinct sequence of perturbations in neocortical development: 1) disruption of the radial glial scaffolding with premature astroglial differentiation, and 2) thickening of the marginal zone with redistribution of Cajal-Retzius neurons to deeper layers. These initial events are followed by disruption of the cortical plate and appearance of subventricular zone nodules. Finally, we observed the erosion of neocortical subventricular zone nodules into the hippocampus around parturition followed by migration of nodules to hippocampus. We conclude that prenatal MAM exposure disrupts critical developmental processes and prenatal neocortical structures, ultimately resulting in neocortical disorganization and hippocampal malformations.
authors.affiliation: Epilepsy Research Laboratory, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Paredes
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Pleasure
authors.forename: Scott C
authors.initials: SC
authors.lastname: Baraban
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000187:drug effects / Q000503:physiopathology; D002828:Choristoma / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006624:Hippocampus / Q000002:abnormalities* / Q000187:drug effects / Q000503:physiopathology; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives; D009421:Nervous System Malformations / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D013723:Teratogens
chemical_list: D013723:Teratogens; D008746:Methylazoxymethanol Acetate; C030667:methylazoxymethanol