The primary research objective is to examine the relation between ontogeny of synaptic physiology and epileptogenicity in the mammalian neocortex. The hypothesis to be tested is that peak vulnerability to seizures coincides with hyperdevelopment of pathways including transcallosal projections. Issues to be examined include: 1) Characterization of synaptic responses at different ages to deep white matter and corpus callosum stimulation. 2) Defining the ontogeny of propagation patterns of epileptic discharge which may indicate the efficacy and extent of excitatory connectivity. 3) Characterization of development of inhibitory postsynaptic potentials and responses to gamma-aminobutyric acid (GABA). 4) Gaining insight into mechanisms underlying seizure spread and generalization and the influence of developmental changes in synaptic organization to such mechanisms. These studies will utilize unique neocortical slices consisting of portions of both cerebral hemispheres containing homotopic areas of cingulate and sensorimotor cortex connected by an intact corpus callosum. Experiments aimed at identifying responses to GABA will use dissociated neocortical neurons. The novel slice preparation lends itself to studies in which differential pharmacological manipulation of each hemisphere will be possible. These studies have direct implications for the role of synaptic development in seizure susceptibility, and they will help specify particular inhibitory or excitatory mechanisms which underly the changing vulnerability of the immature brain to epilepsy. In addition, valuable information will be gained about such issues in normal animals.
