Excitatory

AA Neurotransmission
What are the EAA candidates?
Glutamate is formed by this krebs cycle
intermediate.
Note: metabolic pool and NT pool for glutamate are
strictly segregated from one another.
Asapartate is formed from the kreb cycle
intermediate
Aspartate is documented as the NT of which cells?
Of what cortex?
What are the major ionotropic receptors?
Activation of NMDA receptors allows enterance of
what ions?
What are the endogenous ligands that bind NMDA
receptors?
What are OTHER ligands that bind the NMDA
receptor? Describe these binding sites. (5)

What activates the AMPA receptor?

Activation of AMPA receptor allows enterance of
what ions?
The AMPA receptor has a modulation site for which
class of drugs?
What is the effect of the above?
What activates the Kainate Receptors?
What ions does the above channel allow in?
Note: metabotropic receptors general mode of
action:
1. Some decrease cAMP
2. Some increase IP3/DAG
3. ONE increases cAMP
Antibodies against the metabotropic receptor (and
a subtype of NMDA receptor) has been found in
humans suffering from

Glutamate and Aspartate or combo of the two
(NAAG)
a-ketoglutarate

Oxaloacetate (OAA)
Pyrimidal cells and spiny stellate cells of visual
cortex
NMDA and AMPA receptor (+also kainate receptor)
Ca2+ (but also Na+) Ca determines major effects
n-methyl-d-aspartate (nmda) and aspartate,
glutamate
1. Glycine binds to GLYCINE BINDING SITE
[extracellular] (yes the inhibitory AA)
acts as co-agonist w/ primary ligand.
2. pH SENSITIVE REGION [extracellular] pH
decreases H+ increases blocks opening
of channel
3. Zinc Binding Site [inside channel]
modifies Ca2+ influx
4. PCP Binding Site [inside channel/gate]
common site for drugs blocks Ca2+ influx
5. Mg Binding Site [inside channel] blocks
channel @ resting membrane potential
leaves site and allows Ca2+ influx w/
depolarization of cell
AMPA (exogenous), glutamate and aspartate
Mainly Na+ influx
Benzodiazipines
Blocks Na influx
Kainate, Glutamate and Aspartate
Primarily Na+ but also some Ca2+

Rasmussens Encephalopathy (seizures destroy one

hemisphere of brain Tx: remove affected
hemisphere)

Describe EAA removal from the synapse:

What happens if (1) loses its gradient?

Most primary efferents in spinal cord are due to
EAA action on which receptor class?
EAA at NMDA receptors are found throughout..
EAA at NMDA receptors is believed to be involved
in producing
EAA at metabotropic receptors is widely
distributed throughout
What is the general effect of EAA at metabotropic
receptors?

By astrocytes (glial cells) and neurons 3

different transport systems (1) Na dependent
secondary active transport . High Affinity
Systems.

In astrocytes Glutamate-Glutamine cycle.
Astrocytes take up glutamate convert to
glutamine via glutamine synthetase (req ATP)
glutamine released back into EC space for neuron
to take it up in neuron converted back to
glutamate becomes second source of glutamate
for neurons.
Uptake is slowed down if Na gradient is lost
Non-NMDA
CNS (most attn. paid to hippocampus)
Long term changes in synaptic strength via process
known as LTP (long term potentiation) + memory +
learning
CNS

Decrease in synaptic excitability

Also involved in synaptic plasticity [learning +
memory] (along with NMDA receptors)
What might be the effect on mice missing mGLUR1 Suffer from motor incoordination and spatial
(metabotropic receptor)
learning problems
Note: Some metabotropic receptor antagonists may
actually IMPROVE some forms of learning!
Nitric Oxide is produced due to direct result of this NMDA receptor activation
receptor class activation:
How does the above result in NO production?
NMDA receptor activated Ca2+ influx
activation of Calcineurin (phosphatase) cleavage
of phosphate group from NO synthase NO
synthase activated! NO synthase cleaves NO off
of ARGININE NO produced!
What are some actions of NO regarding a cyclase?
(1) NO activates guanylyl cyclase increase in
cGMP
NO Ca2+ dep. K+ channel activation
What is the effect of (1) from above?
Causes smooth muscle relaxation
Before being IDd as NO. What was it called?
Endothelium-derived relaxing factor (EDRF)
What is its action in the GUT?
Inhibitory causes relaxation
Role of NO in CNS?
1. Respiratory Control
2. Cardio Control
3. Memory/Learning (LTP)
What is the NON neuron role of NO in the CNS?
NO causes cerebral vasculature relaxation due to
higher neuronal activity (this increases blood flow)
ADD NOTES FROM PG 33 4

How is NO removed from synapse?
No uptake system NO life is 5 seconds can
bind to hemoglobin
EXCITOTOXICITY

EAA induced brain damage best evidence:

1. Domoic acid poisoning from contaminated

mussels. BEST EVIDENCE
2. Cerebral Ischemia/stroke
3. Hypoxia or anoxia
4. Mechanical trauma to CNS
5. Hypoglycemia
6. Epileptic seizures
What are the events leading to cell death following Rapid reduction in ATP in cells cell
ischemic insult? WITH ISCHEMIA?
depolarization due to dysfunctional Na/K ATPase
presynaptic NTs released high levels of NTs
(EAAs) enter synapse XS activation of non-
NMDA and NMDA receptors
-XS is reinforced since EAA reuptake is dep. on Na+
concentration gradient. With ATP depletion Na
gradient decreases and reuptake mechanism fails.
Step 1:
Increase in intracellular Ca2+
1. XS NMDA receptor activation XS Ca2+ influx
Step 2:
Activation of enzymes by Ca2+
1. Activation of Phospholipase A2 inside cell
2. Activation of Calcineurin (phosphatase)
3. Activation of mu-calpain (protease)
4. Activation of apoptotic cycle
In step2: depolarization itself activates
Phospholipase C
Step 3:
Deranged cellular metabolism following enzyme
activation
What is the effect of the enzyme activation on the
Phospholipases damage cell membrane AA
cell membrane?
released
What is the effect of AA released on intracellular
AA acts on organelles like mitochondria and ER to
Ca2+? How?
cause further Ca2+ efflux and causing these
organelles to fail.
Note: Phospholipases act on cell membrane to release AA from cell membrane physical damage to
membrane AA also acts on organelle ryanodine receptor to cause further Ca2+ release (ER,
Mitochondria) even higher Ca2+ levels intracellularly organelles fail due to efflux of Ca2+.
What is the result of mu-calpain activation?
Damage to cell structure and proteins (ie. elF4G
and spectrin)
What is the effect of calcineurin activation?
XS NO is made due to hyperactivity of NO synthase
Step 4:
Induction of apoptotic pathway
How is the above initiated?
Damage to mitochondria causes release of
cytochrome c and caspase 9 + APAF-1 causes
activation of caspase 3 CASPASE 3 = APOPTOSIS
Reperfusion Injury

How does reperfusion cause injury when it seems
Circulation re-established neuron takes up O2
like it should actually be a good thing?
neuron has a lot of Ca2+/NO running around in it
but no ATP and damaged mitochondria O2 not
taken up my mitochondria produces PEROXIDE
RADICALS leads to lipid/membrane damage.
How is protein synthesis disrupted in reperfusion
The original efflux of Ca2+ from ER causes
injuries?
activation of elF2alpha kinase this
phosphorylates elF2alpha which is INHIBITORY to
protein synthesis.

In the above situation, protein synthesis was

already impaired due to damage to which protein?
What are the other actions of elF2alpha once its
phosphorylated?
Delivery of blood borne chemicals to cell
contributes to reperfusion injury. Describe how
epinephrine contributes:
Describe how influx of WBCs contributes:
What receptor does histamine bind to in order to
cause further influx of Ca2+
What is the net result of influx of growth factors
(insulin included)?
What is effect of EPI on insulin?
What is the specific effect of blood flow alteration?

elF4G (by mu-calpain)

Activates caspase 3, activates CHOP (leads to
apoptosis)
Epinephrine beta-receptor on neuron
increase in cAMP increases extracellular K+
cell depolarizes further PKA activated
elF2alpha phosphorylated MORE INHIBITION
TO PROTEIN SYNTHESIS
Ischemic event endothelial cells express cell
adhesion molecules WBCs recruited to area
NO release + histamine (causes further Ca influx)
NOT mediated by any known histamine receptor

The cells cannot respond to the growth factors due

to cell damage.
It reduced efficacy of insulin signaling
Reactive hyperemia due to O2 deprivation leads to
vasodilation (most likely NO)
What is non-specific effect of blood flow alteration? Vasodilation due to XS NO from NMDA receptor
activation (XS) and activated WBCs
What happens to vascular permeability as a result Increases
of the reperfusion injury?
What is the consequence of the above?
Edema due to fluid leaking brain swells
intracranial pressure increases neurons killed
blood flow blocked