GANGLIOSIDES AND DENDRITOGENESIS IN CORTICAL DEVELOPMENT

DESCRIPTION (Verbatim from the Applicant's Abstract: One of the most profound events in the life of a neuron in the mammalian CNS is the development of the dendritic tree, yet little is understood about the events controlling this process. Under normal circumstances dendrites emerge from neurons during early brain development and form a characteristic dendritic arbor which is maintained throughout the life of the individual. Cortical pyramidal neurons, for example, undergo dendritic differentiation after completing migration to the cortical mantle. A period of explosive sprouting and elaboration of dendritic processes is followed by a period of pruning and shaping. For normal pyramidal neurons there is no evidence that new, primary dendritic sprouting occurs later in development. Yet in one group of rare genetic diseases--Tay-Sachs disease and related neuronal storage disorders--cortical pyramidal neurons do undergo a second phase of dendritogenesis. New dendritic membrane is generated principally at the axon hillock area and in time this membrane is covered with normal appearing dendritic spines and synaptic contacts. These "ectopic" dendrites thus form a secondary basilar dendritic system on affected neurons. In our studies of neuronal storage diseases we have discovered that neurons exhibiting ectopic dendrite growth always have one feature in common: They contain elevated levels of GM2 ganglioside. Furthermore, all evidence suggests that the elevation in this ganglioside precedes the formation of these ectopic dendrites. Armed with this discovery, we have recently explored GM2 expression during normal dendritogenesis in the immature brain. Again, GM2 ganglioside is abundantly expressed at precisely the time when normal dendritic sprouting is occurring, and as dendritic trees mature, GM2 expression decreases. GM2 ganglioside is essentially undetectable in most neurons of the normal, mature cerebral cortex. These findings have led us to hypothesize that GM2 ganglioside is a pivotal modulator of cellular mechanisms controlling dendritic outgrowth in cortical pyramidal neurons. The goal of this research proposal is to rigorously test this hypothesis in the normal, developing cerebral cortex using a combination of in vivo and in vitro studies.