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| examination
of the process of experience dependent
modification (or plasticity) of synapses
at the cellular and molecular levels |
|
David Wells, Ph.D.
Assistant Professor of
Molecular, Cellular and Developmental Biology
Email: david.wells@yale.edu
B.A. University of Vermont
1986; Ph.D. University of Vermont 1994 |
The formation and maintenance of memories is
one of the brains most intriguing functions. Somehow
encoded into the neural circuitry is the ability
to store and retrieve experiences for years or
even decades. Since synaptic transmission encodes
information in the brain, the engram for memory
may lie in the ability of the synapse to use stable
modifications to remember its excitatory history.
The focus in our lab is to examine this process
of experience-dependent modification (or plasticity)
at the cellular and molecular level.
A critical step in long-lasting synaptic plasticity
is the production of new proteins. Synapses undoubtedly
use proteins that are generated in the cell body
and subsequently transported into the dendrites;
however, there is increasing evidence that local
(dendritic or even synaptic) protein synthesis
plays a crucial role in long-lasting synaptic
changes. We have known for over 20 years that
mRNA is present in dendrites, but mechanism(s)
for translational regulation are only now being
elucidated.
Our lab examines a molecular mechanism capable
of regulating mRNA translation in dendrites. This
process is dependent on an mRNA binding protein
called CPEB that is present in neurons and localized
to synapses. CPEB was first described in Xenopus
oocytes where it regulates mRNA translation through
poly(A) tail elongation. We have shown that polyadenylation
of specific messages in the visual cortex and
hippocampus occurs following neural activity and
is concomitant with an increase in the encoded
protein at the synapse. Our lab is currently studying
this mechanism in neurons throughout the brain
to determine if this process is a general mechanism
for experience dependent plasticity.
We use a combination of molecular, cellular and
electrophysiological techniques to address how
CPEB-mediated protein synthesis is initiated and
what mRNAs this process regulates.
Selected Publications
Wells, D.G. and J.R. Fallon. (1996) Neuromuscular
junctions: The state of the union. Current
Biology 9:1073-1075.
Wu, L.*, Wells, D.*, Tay, J., Mendis, D., Abbott,
M-A., Barnitt, A, Quinlan, E., Heynen, A., Fallon,
J.R., and Richter, J.D. (1998) CPEB-mediated cytoplasmic
polyadenylation and the regulation of experience-dependent
translation of a-CaMKII mRNA at synapses. Neuron
21:1129-1139.
Wells, D.G., B. McKechnie, S. Kelkar and J.R.
Fallon. (1999) Neurotrophins regulate agrin-induced
postsynaptic differentiation. Proceedings of
the National Academy of Sciences 96:1112-1117.
Abbott, M-A., D.G. Wells and J.R. Fallon. (1999)
The insulin receptor tyrosine kinase substrate
p58/53 and the insulin receptor are components
of CNS synapses. Journal of Neuroscience
19:7300-7308.
Wells, D.G., J.D. Richter and J.R. Fallon (2000)
Molecular mechanisms for activity-regulated protein
synthesis in the synapto-dendritic compartment.
Current Opinion in Neurobiology 10:132-137.
Wells, D.G. and J.R. Fallon (Submitted) In search
of molecular memory. Cellular and Molecular
life sciences.
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