Project: Research project

Project Details


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.
Effective start/end date8/1/997/31/02


  • Genetics(clinical)


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