Protein kinase C-dependent phosphorylation in prenatally induced microencephaly.

We describe here integrated studies conducted in an animal model of brain malformation induced by prenatal treatment with a potent antimitotic agent, methylazoxymethanol acetate (MAM). When given at gestational day 15, MAM induces a marked and dose-dependent hypoplasia of cortex and hippocampus. The alteration of specific neurotransmitter systems in these brain areas reflect the specificity of the damage induced by MAM administration at this particular stage of brain development. These animals, when adult, show impairments in learning and memory performance, without gross alterations of spontaneous behavior. The impairment in cognitive functions is correlated with changes, both in cortex and hippocampus, of the phosphorylation state of the neuron-specific protein B-50, a substrate of Protein Kinase C, known to play a key role in synaptic plasticity. Moreover, Long-Term Potentiation (LTP), a cellular model for studying synaptic plasticity associated with learning and memory, is impaired in the hippocampal subfields affected by MAM treatment. All these results--obtained with anatomical, behavioral, neurochemical and electrophysiological studies-point to the usefulness of this animal model to understand the long-lasting consequences of the interference of neurotoxic compounds with the developing CNS.