Transcript The Synapse - University of Toronto

The patient
and her
problem:
The patient and her problem:
Aneurysms can be treated by
applying a clip to the “neck”
Aneurysm
Aneurysms can be treated
by applying a clip to the
“neck”
Aneurysms can be treated
by applying a clip to the
“neck”
However, if they get too big:
1. Danger of the clip occluding the parent artery
2. Can’t see around the aneurysm to clip it safely
Our patient failed a “test balloon occlusion” of
her ICA. Therefore, cannot afford to lose the
artery, or to have it clamped off for prolonged
perionds of time.
Need to devise a strategy to
protect the brain from the lack
of blood flow (ischemia)
during the surgery.
Concepts of ischemia
Concepts
of
ischemia
John Olney &
The Excitotoxicity
Theory:
Glutamate as a
neurotoxin
Glutamate receptors &
Ischemia
Glutamate receptors
Glutamate evokes a 2component EPSP
AMPA (rapid)
NMDA (slow)
Ionotropic glutamate
receptors
• Are associated with an ion channel
• N-methyl-D-aspartate (NMDA): composed of 4 or 5
subunits (NR1 and NR2a,b,c,d)
• -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA): composed of 4 or 5 subunits (GluR1-4)
• Kainate receptors: GluR5-7, KA1-2
These receptors are presumed to have different
physiological functions.
Glutamate also activates
metabotropic receptors
These are glutamate receptors that do not contain an ion
channel.
These receptors, when activated, act by initiating 2nd
messenger cascades that result in the mobilization of
intracellular Ca 2+ stores.
The role of these receptors is less clear than ionotropic
receptors (NMDA and AMPA), but is felt to be importante
in neuronal function and dysfunction.
Glutamate receptors are
strategically localized in the
synapse
NMDA receptors on a cortical neuron
NMDA receptors on a cortical neuron
AMPA receptors on a cortical neuron
AMPA receptors on a cortical neuron
Molecular Model of the Postsynaptic Density at a Central Excitatory Synapse
Organization of the PSD
Hypothetical organization of
presynaptic (NT, nerve terminal)
and postsynaptic (SP, spine)
structures. Synaptic vesicles (orange
spheres) release glutamate into the
synaptic cleft, which in turn
stimulates NMDA (blue rectangle),
AMPA (red, yellow rectangle), and
metabotropic (brown membrane
protein) glutamate receptors. In the spine, actin cables (vertical pink
filaments) are linked to brain spectrin (red, horizontal molecules). Also
present in the spine are endoplasmic reticulum (blue membranous structure)
and calmodulin (green ovals). Numerous kinases and proteases are not
shown because their localization is not established.
PSD details:
TrkB responds
to BDNF (pink
receptor; blue
ligand).
The neuroligan (green rectangle)
cytoplasmic domain binds PSD95 (blue, green, yellow ovals).
PSD-95 binds GKAP/ SAPAP/
DAP protein (red) and the NMDA
receptor (blue rectangle), which
in turn binds -actinin (orange)
and actin (pink).
Two AMPA receptors (red,
yellow rectangle) are shown.
Each binds GRIP, which has
seven PDZ domains (red
circles). Dimerization of GRIP
via N termini is hypothetical.
Effect of calcium:
Ca2+ that enters the spine through the NMDA receptor in response to receptor
binding of glutamate (yellow circle) is proposed to activate calmodulin (green oval),
which displaces  -actinin and actin (orange oval, pink chain) from the NMDA
receptor NR1 subunit C terminus.
Why Glutamate Receptors are
Important in Neurology:
Glutamate is present in millimolar quantities in most cells,
including neurons and glia
Glutamate is the main excitatory neurotransmitter in the
mammalian CNS
Glutamate is released in large quantities during
• Stroke
• Trauma
• Epilepsy
• Possibly in chronic neurological disorders
Why Glutamate Receptors are
Important in Neurology:
Excess glutamate is released at the synapse through
• Synaptic activity
• Reverse operation of glutamate transporters
• Reduced re-uptake (due to reduced ATP levels)
Glutamate levels may rise at the synapse to hundreds of
micromolar, which is enough to cause excitotoxicity
What happens to neurons with
excess glutamate?
Normal Neuron
What happens to neurons with
excess glutamate?
• Cell Swelling
• Dendritic
Beading
• Axons: no
change (?)
Glutamate
Excess glutamate kills neurons through Ca2+ overload
Ms. M.O., 47 yrs old.
Admitted to
hospital 7 days
after a sudden,
severe,
headache, with
Rt sided
paralysis
Ms M.O.
Vs
Concept of vasospasm after SAH
Mrs S.N.
Ms. M.O., 47 yrs old.
Admitted to
hospital 7 days
after a sudden,
severe,
headache, with
Rt sided
paralysis
Ms. M.O., 47 yrs old.
Admitted to
hospital 7 days
after a sudden,
severe,
headache, with
Rt sided
paralysis
Ms. M.O., 47 yrs old.
Ms. M.O., 47 yrs old.
Ms. M.O., 47 yrs old.
Decompressive craniotomy
Last 2 lectures:
Continue on why glutamate toxicity is important in
neurological diseases
Learn about Calcium Homeostasis in cells and why it is
important
Devise, based on what we have learned, strategies to
protect the brain neurons and axons against stroke
Find out what we did to prevent stroke for our patient with
the giant aneurysm
Show a short video of how an aneurysm gets fixed
Cover the brain’s other cells, and how they might be
important.