Plasticity, the modulation of activity as a result of
experience, is a fundamental feature of brain function.
It is manifested at many levels of organization, including
behavior of the organism, output of large neural networks,
and properties of individual nerve cells and of the synaptic
connections among them. The molecular mechanisms involved
in synaptic plasticity have been widely studied in recent
years, and this has emerged as one of the most active
and exciting areas of research in modern cellular neurobiology.
Although diverse molecular pathways have been implicated
in synaptic plasticity, one common theme that has emerged
is that calcium plays a central role.
Calcium can enter neurons in a variety of pathways, including
several kinds of calcium channels and some ligand-gated
ion channels. The Tsien laboratory has been in the forefront
of studies of calcium for many years, and has played a
key role in defining calcium channel diversity. A major
challenge for neurobiologists is to define the roles these
different calcium entry pathways play in neuronal physiology.
More specifically, the role of different modes of calcium
entry in synaptic transmission and synaptic plasticity
is of great interest. Tsien showed in his lecture that
calcium entry through one kind of calcium channel evokes
vesicle fusion at the presynaptic membrane and release
of neurotransmitter into the synaptic cleft. Entry via
another kind of calcium channel does not appear to evoke
neurotransmitter release, but instead signals to the cell
nucleus. A complex cascade leads to the calcium-dependent
phosphorylation of the transcription factor CREB. As a
result of calcium entry, the ubiquitous calcium-binding
protein calmodulin is translocated in the nucleus, where
it activates a particular kind of calcium/ calmodulin
dependent protein kinase. It is this enzyme that in turn
phosphorylates CREB, and allows CREB to activate the transcription
of a number of different proteins. These proteins then
are able to influence the properties of the synapse over
a long period of time. The results described in this lecture
emphasize the richness and complexity of the signaling
pathways that can influence neuronal function.
