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 safelyOur 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 2-component 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 PSDHypothetical 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 membraneprotein) 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 PSD-95 (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 Mrs S.N.Concept of vasospasm after SAH

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. Progressive infarction

Progressive Brain Swelling

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.