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Gelsolin : a regulator of postsynaptic actin assembly and AMPA receptor expression

Zhao, Pingwei. Gelsolin : a regulator of postsynaptic actin assembly and AMPA receptor expression. 2003, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_6840

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Abstract

Dendritic spines are the postsynaptic contact sites for the majority of excitatory
synapses in the brain. Synaptic activity influences the number, shape and
motility of dendritic spines and these effects are likely mediated by dynamic
actin filaments, which are highly concentrated in spine heads. Drugs that inhibit
actin dynamics block spine motility and interfere with the development of longterm
potentiation (LTP), a long-lasting increase in synaptic strength considered
to be closely related to learning and memory. This suggests that actin may
serve as a link between activity-induced modulation of synaptic transmission
and long-term changes in synaptic morphology. Despite this evidence for the
importance of actin dynamics in synaptic plasticity, very little is known about its
regulation at the synapse. In particular the mechanisms linking synaptic activity
to the actin cytoskeleton in dendritic spines are not well understood.
The experiments described in this thesis were focused on gelsolin as a
promising candidate for mediating synaptic activity to actin cytoskeleton in
dendritic spines. It is shown here that exposure of cultured hippocampal
neurons to glutamate results in the accumulation of gelsolin in dendritic spines.
This effect is the consequence of activation of NMDA receptors and influx of
Ca2+. It is also shown that the F-actin binding domain of gelsolin is necessary
for its enrichment at postsynaptic sites. Further experiments showed that actin
filaments are more vulnerable to disruption by glutamate stimulation in gelsolin
over-expressing neurons. The disruption of actin filaments in these neurons is
also dependent on NMDA receptor activation and Ca2+ influx. LTD-related
electric field stimulation likewise increased the loss of filamentous actin in
gelsolin expressing cells compared with untransfected cells. The disruption of
actin filaments required the severing function of gelsolin, which is associated
with the specific filament-severing domain (domain 1) of the gelsolin molecule. Severing of F-actin by active gelsolin reduces the amount of AMPA receptors
(GluR1) associated with dendritic spines.
These results indicate that gelsolin plays an important role in linking synaptic
activity to the postsynaptic actin cytoskeleton. Our results are also consistent
with evidence that activation of NMDA receptors and influx of calcium ions play
a crucial role in regulating the actin cytoskeleton in dendritic spines and hence
are involved in the regulation of postsynaptic glutamate receptor plasticity at
excitatory synapses via a feedback mechanism. This could occur in both the
developing and mature brain under both normal and pathologic conditions.
Taken together, our data support a model in which activity-dependent targeting
of proteins into dendritic spines is a major mechanism for regulating synaptic
plasticity at excitatory synapses.
Advisors:Matus, Andrew
Committee Members:Reichert, Heinrich and Caroni, Pico
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Neurobiology (Schaeren-Wiemers)
UniBasel Contributors:Reichert, Heinrich
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:6840
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:102
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 15:10

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