Spontaneous electrical activity plays a major role in nerve and muscle development. In the vertebrate central nervous system, spontaneous activity is required for the establishment of correct neuronal position, morphology, and connectivity. This spontaneous activity is distinct from later experience-dependent activity: it occurs without sensory input, and in some cases in completely isolated cells. It must therefore be controlled by the ion channels present in individual cells at early stages of development. Supporting this idea are findings that the properties of ion channels present early in development are often markedly different from those in the mature cell. Studies of ion channel development that have provided these ideas have primarily been done in invertebrates and lower vertebrates, whereas many studies of the developmental roles of spontaneous activity have been done in mammalian brain. In fact, there is very little information about the development of ion channel properties in the prenatal mammalian neocortex. The neurons of the cortex arise from divisions of ventricular one progenitor cells, which then migrate into the cortical plate. In mouse, these divisions occur between embryonic days 11 and 17. Our preliminary patch clamp experiments during this neurogenic interval have shown interesting differences in voltage-gated ion channel populations between neural progenitor cells and the radial glia along which they migrate, as well as marked change in Na and K currents as migrating neurons leave the ventricular zone. The proposed experiments use patch clamp to measure ion channel properties, dye fills to determine cell morphology, and immunocytochemistry to determine cell identity, to study the development of voltage-gated ion channels in ventricular zone cells and migrating neurons during the neuronogenic interval in the embryonic mouse. This data will be used to detect periods of development during which the populations of channels present mediate spontaneous activity, and then to develop strategies to block that activity and thus determine its developmental functions. Diseases that disrupt electrical activity in the developing fetal brain, such as epilepsy, are likely to have profound effects, because activity serves a developmental role at early stages, in contrast to its information processing role in the adult. The studies proposed here bear on the mechanisms by which such disruptions occur.
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