Mechanisms in the induction of neuronal heterotopiae following prenatal cytotoxic brain damage.

Abstract

Prenatal exposure to several neuroteratogens, such as ionizing radiation, ethanol, and cytotoxic drugs, induces the development of clusters of abnormally positioned neurons within the brain. These abnormalities have always been presumed to result from interference with normal neuronal migration, presumably via effects on radial glia. In our study, pregnant rats were injected with methylazoxymethanol acetate (MAM) on either E13, E14, or E15. Computerised reconstruction techniques, Golgi and immunocytochemical staining as well as electron microscopy were used to detect structural abnormalities of radial glia which might be responsible for the production of heterotopiae. Several structural abnormalities such as microcavitation, involvement of radial glial elements in rosettes, disturbance of the normal ventricular lining, and disruption of the attachment of radial glial endfeet to the pial surface were identified. We propose that periventricular heterotopiae result from disruption of the palisade arrangement of neuroepithelial cells in the ventricular zone and the involvement of radial glial elements in rosettes. Layer I heterotopiae may arise from abnormalities of the distal segments of radial glia and their attachment to the pia. No prenatal abnormalities in radial glia of the hippocampus were noted following MAM exposure at any of the 3 ages, consistent with the proposition that hippocampal heterotopiae arise by postnatal movements of pyramidal neurons without radial glial involvement.