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Hi.
My name is Giles Hardingham.
I work at the
University of Edinburgh.
And my laboratory is interested
in signal pathways and genes that
control the protection, as well
as the death and dysfunction,
of neurons.
Now, we're particularly interested
in calcium signalling pathways
and how calcium mediates
these kind of effects.
And one particular focus in the
lab is on an important source
of calcium influx, the NMDA subtype
of ionotrophic glutamate receptors.
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So a typical glutamatergic
synapse, such as the one shown
in the cartoon here, the NMDA
receptor is a very important source
of activity-dependent
calcium influx.
What happens is you get
presynaptic release of glutamate
into the synaptic cleft, which
causes postsynaptic depolarization
mediated by the AMPA subtype
of glutamate receptor.
This postsynaptic
depolarization alleviates
the voltage-dependent magnesium
block on the NMDA receptor.
Which when, coincident with
glutamate binding to the receptor,
opens the channel and in flows
sodium, and importantly calcium.
And it's this calcium
that is a major mediator
of the neuroprotective, as well as
the toxic effects of NMDA receptor
activity.
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So before going over more
contemporary research,
I just want to briefly outline
the origins of this field.
And the origins of the field,
the research into the control
of survival and death
by NMDA receptors
can be traced back
to a paper published
in 1957 by Lucas and Newhouse.
And what they observed was that
the amino acid glutamate, when
administered to the retina,
was toxic to the neurons
in the inner layers of the retina.
Now, this work wasn't followed
up until the late '60s, when
John Olney demonstrated
that glutamate could be
toxic to a wide variety of neurons
in different brain regions.
And he coined the term
"excitotoxity" because, of course,
glutamate by then was well known
as an excitatory neurotransmitter,
as well as being potentially toxic.
So it wasn't until the
mid-1980s that the major cause
of glutamate excitotoxity was pinned
down by Choi, Meldrum, and others
as being due to calcium
influx into the neurons.
And that this calcium influx was
mediated by the NMDA receptor,
the NMDA subtype of ionotrophic
glutamate receptors.
And extremely soon
afterwards, it became clear
that NMDA receptor-mediated
excitotoxity was physiologically
relevant because it was implicated
in contributing to neuronal loss
and dysfunction in acute
disorders, particularly
stroke and traumatic brain injury.
And later, it was implicated
in more chronic disorders,
such as Huntington's disease
and Alzheimer's, Abeta
toxicity as well.
So, of course, all this
happened before genes
encoding the NMDA
receptor were cloned.
At the time, researchers still
had pharmacological tools
that could isolate the currents
mediated by the NMDA receptor
and distinguish them from other
types of glutamate receptor,
like the AMPA and kainate receptor.
So the other thing I want to just
go over before we get into more
modern literature is how NMDA
receptor-mediated excitotoxicity
actually takes place.
And regardless of whether
the disorder is an acute one,
such as ischemia, or
a more chronic one,
such as Huntington's, it seems
that loss of glutamate homeostasis
is a key mediator.
