Cellular and Molecular Neuroscience
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At the cellular scale, University of Sydney neuroscientists are
studying the formation and function of synapses – the gaps
between nerve cells that channel traffic on our neural highways.
Equally important are the neurotransmitters that cross between
cells, triggering or suppressing responses, and the molecular
receptors that they target.
While some researchers use mathematical biophysics to focus on
basic questions about the structure and function of transmitters
and receptors, others study links between stress mechanisms and
infant development, and between hormones and diseases like multiple
sclerosis.
More recently, the team discovered that the adult nervous system
has the capacity to form new synapses within minutes, rather than
weeks, as previously thought.The team found that synapses appeared
and disappeared continually in as little as 20 minutes, and immediately
began transmitting impulses. The work may lay the foundations
for new treatments for Alzheimer’s Disease and stroke.
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Research Themes:
J Barden & J
Wiley
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The Nepean Purinoceptor Group
The Nepean Purinoceptor Group has a major focus in exploring
the biology of the human P2X7 receptor. This receptor is highly
expressed in haemopoietic as well as nervous tissue where
it functions as a cytolytic receptor producing apoptotic death
of macrophages, lymphocytes and neurones. Our focus is on
structure-function relationships including a study of single
nucleotide polymorphisms in the human P2X7 receptor and the
effect of these on receptor function and biology of both haemopoietic
cells and nervous tissue. The Group is actively exploring
the down stream signalling pathways from the receptor as well
as the assembly and components of the P2X7 death inducing
complex in the cell membrane. Our Group works closely with
that of Dr Julian Barden (Anatomy and Histology) in exploring
the structure of the extracellular domain of this receptor
and identifying groups essential for the ATP binding pocket.
Finally, we are extending our study of the P2X7 receptor to
examine its role in a variety of human diseases such as chronic
lymphocytic leukaemia, tuberculosis and neurological disease.
Contacts:
Professor James Wiley
Telephone: 02 4734 3277
Dr Julian Barden
Telephone: 02 9351 2679
Biographies:
James Wiley is Professor and Head of Haematology at Nepean
Hospital which is a 420-bed Teaching Hospital at the foothills
of the Blue Mountains. The focus of his research has been
in membrane transport during a long career which has spanned
Oxford, Philadelphia, Melbourne and since 1997 Sydney University.
Julian Barden is head of the Protein Receptor Structure and
the Biosceptre Laboratories in the Dept. of Anatomy &
Histology. The main focus of his research is in understanding
the molecular mechanism of channel gating and the development
of greatly improved diagnostics for the earliest possible
detection of preneoplasia and cancer in most tissues.
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M R Bennett
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The distal extremity of the synaptic nerve terminal
at the mature toad (Bufo marinus) neuromuscular junction
grows over short periods of time. The nerve terminal (red,
top) and Schwann cell (green, middle) were filled
by iontophoretic injection with different flourescent dyes and
imaged on a confocal microscope.
The overlay image (bottom) shows the
two fine nerve terminal processes enclosed in corresponding
Schwann cell processes. The smaller of the two processes was
observed to grow over the course of twenty minutes. Such
new processes can form functional synapses within this short
period.
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The Neurobiology Laboratory
The Laboratory is concerned with elucidating the mechanisms
involved in the formation and functioning of synapses in the
peripheral nervous system. Autonomic neuromuscular junctions
and synapses in autonomic ganglion cells are the principal preparations
used in this research together with somatic neuromuscular junctions.
The following problems are under active investigation at this
time:
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Identification of factors that determine the probability
of quantal secretion at nerve terminal release sites.
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The effects of calcium on vesicle-associated proteins in
nerve terminals.
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Elucidation of the mechanisms governing the transient increase
in probability of transmitter release following
an impulse.
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Autoreceptor control of the probability of transmitter
release following an impulse.
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The mechanism of action of the new class of transmitters
exemplified by nitric oxide.
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Development of the probability for secretion at nerve terminals.
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Identification of the calcium initiated apoptotic changes
that trigger neuronal cell death.
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Link To Laboratory -
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W G Gibson
mathematical biophysics of synaptic transmission.
P Jeffrey
isofrom sorting in intracellular domains.
W Phillips
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Connections between nerve and muscle underlie movement and
life. Our research seeks a clearer picture of how proteins on
the muscle side of these synapses (the postsynaptic membrane)
work together to organise the synapse. Receptors in the specialised
postsynaptic part of the muscle cell membrane receive chemical
and nerve-activity signals that allow it to adapt, increase
or decrease its responsiveness to nerve activity and provide
support and encouragement to presynaptic nerve terminals.
One of the great challenges for 21st century Neuroscience is
to better understand the cooperative interactions between pre-
and postsynaptic cells, interactions that happen at synapses.
The neuro-muscular junction, with its highly organised structure,
easily studied behaviour and relatively well defined molecular
composition offers great advantages in studying these essential
processes.
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Link to Laboratory -
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We are engaged in studies to:
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Identify the molecular interactions of proteins in the
postsynaptic membrane
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Determine the subcellular pathways by which synaptic proteins
are targeted to postsynaptic membrane domains in living
cells
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Define the role that phosphorylation of key postsynaptic
proteins has in controlling the organisation of the synapse
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Clarify the nature of fast purinergic transmission at neuro-muscular
synapses in smooth muscle tissues such as the vas deferens
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PJ Robinson
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Research at the Cell Signalling Unit at the
Children’s Medical Research Institute is aimed at understanding
the molecular mechanisms of synaptic transmission.
Synaptic vesicles fuse with the wall of the nerve
terminal to release their neurotransmitters (exocytosis) and
are then retrieved to be refilled and re-used (endocytosis).
Work in our Unit is targeted at understanding the molecular
machinery underlying this process.
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Endocytosis is controlled by the protein dynamin. A remarkable
mechanochemical enzyme that is able to assemble as a helix
and undergo rapid helix expansion to pop vesicles back into
the neuron.
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Endocytosis may be regulated by a cycle of protein phosphorylation
and dephosphorylation involving protein kinase C and calcineurin,
and also by lipid phosphorylation and dephosphorylation
involving PI 3-kinase and synaptojanin. These mechanisms
allow reversible targeting of endocytic proteins to sites
of active endocytosis and allow the formation of large endocytic
protein complexes.
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Exocytosis is regulated in multiple and complex manners.
We have found new forms of exocytosis termed “kiss-and-run”
that may increase the efficiency of synaptic transmission.
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The amount of exocytosis may be modulated by signalling
pathways involving cGMP or nitric oxide, and these actions
may be mediated by cGMP-dependent protein kinase and its
nerve terminal substrates like G-septin.
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The sites of exocytosis in the nerve terminal may be directed
by a complex of proteins called the exocyst, which is activated
by the small GTPase RalA.
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Go To Laboratory -
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M Thomson
adrenocortical hormones and their role in multiple sclerosis.
P Wynn
central stress related mechanisms and imprinting in neonates.
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© 2001, The University
of Sydney
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