DEVELOPMENTAL MODELS OF BRAIN DYSFUNCTIONS INDUCED BY TARGETED CELLULAR ABLATIONS WITH METHYLAZOXYMETHANOL

Abnormal brain development represents one of the major causes of neuro logical disorders in humans, and determining the factors responsible f or generating specific brain malformations represents a formidable tas k for developmental neurobiology. The knowledge of the precise neuroge netic time table and the use of toxins, like methylazoxymethanol, able to interfere with neuroepithelial cells entering their last mitotic c ycle, have allowed for targeted neuronal ablations in specific brain a reas of the central nervous system (CNS) when administered at differen t gestational or postnatal days in various animal species. Of particul ar relevance are the studies in which ablations of neuronal population s of cortex, hippocampus, and cerebellum have been made. The results o btained show that these early ablations induce a number of neuroanatom ic, neurochemical, and electrophysiological changes that give us the p ossibility to unravel the biochemical strategies utilized by surviving neurons to adapt to the perturbated environment. Most striking are th e findings that target deprivation does not affect the survival of aff erent neurons in the CNS (except for neurons of the lateral geniculate nucleus), in sharp contrast to the notion of target dependence for pe ripheral nervous system neurons. Animals showing selective ablations i n the Ammon's hom of the hippocampus allow us to understand the comple x biochemical pathways leading to changes in activity-dependent synapt ic plasticity, and the data underscore the fundamental role of diverse Ca2+-dependent protein kinases, and their substrates, in modulating p re- and postsynaptic events during induction and maintenance of long-t erm potentiation (LTP). Because LTP represents a useful model to study molecular substrates of learning and memory, this animal model might be of relevance in understanding cognitive brain dysfunctions.