Glutamate Receptors:

Learning, Memory,

Outline
Glutamate receptors & excitotoxicity:
NMDA-R antagonist as therapeutics

Excitotoxicity & Seizures

Glutamate receptors & Learning, memory,
long-term potentiation: Can increasing the
effect of glutamate enhance cognition?

Glutamate Receptors
Glutamate: major excitatory neurotransmitter in brain
AMPA receptor
agonist: glutamate, AMPA, Quisqualate; Antagonist: NBQX,
CNQX
Na+ & K+ permeable, low Ca2+ permeability, not blocked by Mg2+
Can be activated at all membrane potentials; fast EPSP

NMDA receptor:
agonist: glutamate, aspartate, NMDA; co-agonist: glycine;
antagonist AP-5; channel blocker: PCP, ketamine, memantine

Calcium

Na+, K+ & highly Ca2+ permeable, blocked by Mg2+

Can be activated only at depolarized potentials; slow EPSP
Excitotoxicity

Seizures

NMDA Receptors & Calcium

DiatomRed Tide
Domoic Acid

Glutamate

Learning
Memory

Excitotoxicity,
Seizures
Seizures,
Death

Excitoxicity

Mechanisms of Excitotoxicity
& Cell Death
Glutamate:
activates AMPA R
depolarizes cell membrane
permits Ca2+ entry through
NMDA R & voltage-activated
calcium channels
Ca2+

Ischemic Stroke:
Clot prevents blood flow,
O2 & glucose to brain
Also caused by:
Head injury,
Hypoglycemia
Repeated intense seizures
(status epilepticus)

Energy-dependent
reuptake of glutamate
from synaptic cleft is
reduced.

Glutamate causes
cytoplasmic Ca2+,
neurotoxicity & cell death.
TOO
MUCH
CALCIUM

Ca2+ entry:
Overloads mitochondrial and
ER mechanisms to remove
cytoplasmic Ca2+
Activates proteases & lipases
Creates reactive oxygen
species, free radicals,
damages lipids, proteins &
DNA.

Pharmacological Treatment for Stroke:

NMDA Receptor Blockers:

Aspirin: reduces clot formation, inhibits platelet

thromboxane production which reduces platelet
aggregation
tPA (tissue plasminogen activator): clot buster; catalyzes
breakdown of plasminogen to plasmin, which
proteolyzes fibrin; administered within 3 hrs of stroke
Inhibit NMDA receptor?

Excitotoxicity

Block of Excitotoxicity:
Memantine as Treatment
for Alzheimers Disease

NMDA Receptors & Calcium

Memantine binds in pore & blocks open

NMDA Receptor channel
Unlike PCP and ketamine, it has a fast
off rate and lower affinity, so doesnt
block normal synaptic transmission, but
does block excessive glutamate
stimulation.

Learning
Memory

Excitotoxicity,
Seizures

Learning, Memory & Long-term potentiation:

The hippocampus is a brain region involved in learning
Activation of NMDA receptors is required for learning

Morris
Water
Maze

Or with
NMDA
antagonist

High Frequency
Stimulation Causes Long
Term Potentiation (LTP)

Calcium

LTD:
Endocytosis of
AMPA receptors
from plasma
membrane of
dendritic spines

LTP:
Insertion of AMPA
receptors into
plasma
membrane of
dendritic spines

High Frequency Stimulation Causes Delivery of AMPA Receptors to Dendritic Spines

High Frequency Stimulation
Green fluorescent protein

AMPA R
subunit
AMPA R delivered
to spine

Delivery of AMPA-R to Spines is Blocked by NMDA-R Antagonist (APV)

AMPA Modulators as Therapeutics:

Ionotropic receptors desensitize in
continued presence of agonist
+ Ampakine

Agonist binds to desensitized receptor with

higher affinity, but receptor doesnt open

Glutamate

AMPA modulators ampakine or aniracitam

slow desensitization
desensitization

Enhancement of AMPA responses

enhances attention, learning & memory; a
new approach for cognition enhancers
(nootropic drugs)

Closed

Open

What happens downstream of calcium

influx through NMDA-R to cause LTP?
Calcium activates both
Ca2+/calmodulin kinase II and
protein kinase C
These kinases phosphorylate
substrates, including AMPA-R,
which increases AMPA-R insertion
into the spine plasma membrane

How can downstream signaling

pathways be studied?
Measure activation of CaMKII
using fluorescent CaMKII reporter
At the same time, apply a caged
glutamate agonist, and release the
glutamate with a laser flash to
locally increase [glutamate] in one
dendritic spine

Desensitized

Glutamate

Summary

Glutamate: major excitatory neurotransmitter in brain

AMPA receptor

NMDA receptor:

agonist: glutamate, aspartate, NMDA; co-agonist: glycine; antagonist AP-5; channel blocker:
PCP, ketamine
Na+, K+ & highly Ca2+ permeable, blocked by Mg2+
Can be activated only at depolarized potentials; slow EPSP

Excitotoxicity: ischemia or trauma leads to glutamate, Ca2+ influx & cell death

agonist: glutamate, AMPA, Quisqualate; Antagonist: NBQX, CNQX

Na+ & K+ permeable, low Ca2+ permeability, not blocked by Mg2+
Can be activated at all membrane potentials; fast EPSP

tPA to treat stroke;

NMDA antagonists as therapeutic for Alzheimers & potential therapeutic for stroke, trauma

Long-term potentiation:

The hippocampus is a brain region involved in learning

Activation of NMDA receptors is required for learning
Train of stimuli activates AMPA R which depolarizes the membrane & relieves the Mg2+ block of
NMDA R.
NMDA R allow Ca 2+ influx, which initiates signaling cascades that cause long term increase in
synaptic strength
Redistribution of AMPA receptors into dendritic spines underlies LTP (insertion of AMPA R) and
LTD (retrieval of AMPA R)
AMPA R positive modulators as therapeutics for cognition enhancers (nootropic drugs)