Glutamate and GABA

Question 1

GABA

Answer 1

GABA is the chief inhibitory neurotransmitter in the brain.
- Reduces excitability of cells;

Question 2

Glutamate

Answer 2

Glutamate is the main excitatory neurotransmitter in the
brain.
- Is present in more synapses than any other neurotransmitter
(that we know of)

Question 3

Glutamate is synthesized from the

Answer 3

the conditionally
essential amino acid glutamine.

Question 4

Glutamine can be manufactured in

Answer 4

the body

Question 5

Glutamine is involved in … detoxification

Answer 5

ammonia

Question 6

Neurons can transform glutamine into glutamate
using an enzyme called

Answer 6

glutaminase

Question 7

Once synthesized, glutamate is packaged into…. by …

Answer 7

Once synthesized, glutamate is packaged into
vesicles by three different proteins

VGLUT1, VGLUT2 & VGLUT3;
- Together, these proteins are called vesicular
glutamate transporters (VGLUT)

Question 8

In order to identify glutamatergic neurons, we look
for

Answer 8

VGLUT

Question 9

Glutamate, like other neurotransmitters, is released
following a rise in

Answer 9

intracellular Ca2+ levels

Question 10

Following release, glutamate is rapidly taken back into the
presynaptic cell by a family of five different transporter
proteins:

Answer 10

excitatory amino acid transporters (EAATs)
- EAAT1  5, each with different cellular localizations;
- Astrocytes (EAAT1,2) take up more glutamate than do neurons;
- Major neuronal glutamate transporter is EAAT3;
- EAAT4 are common on Purkinje cells

Question 11

After astrocytes have taken up glutamate, they convert a major portion of it back to glutamine via

Answer 11

glutamine synthetase

Question 12

Once released into the synaptic cleft,
glutamate has threecionotropic post-synaptic
receptors to bind to:

Answer 12

1. AMPA receptors  inward, fast current;
2. NMDA receptors  inward, slow current;
3. Kainate receptors  inward, fast current.

Question 13

All 3 ionotropic post-synaptic
receptors allow Na+ entry into the cell, and therefore cause

Answer 13

depolarization and excitatory
postsynaptic responses

Question 14

Arguably the most important
physiological function mediated
by glutamate is

Answer 14

synaptic plasticity
- Changes in the strength of
synaptic connections between
2+ neurons;
- Learning & memory;
- Long-term potentiation (LTP);
- Implicated in chronic drug use,
addiction, withdrawal, etc.;

Question 15

Kainate receptors, likewise, are ionotropic receptors
permeable to

Answer 15

Na+ and can depolarize a cell.

Question 16

Both AMPA and Kainate (and NMDA) receptors are
comprised of four subunits that come together to form a

Answer 16

receptor channel

Question 17

(NMDA) receptors
are distinct from AMPA and Kainate receptor
subtypes in several ways

Answer 17

1. Permeable to Ca2+ and Na+, and can therefore
   trigger Ca2+ dependent 2nd messenger systems;
2. Opening of NMDA requires a co-agonist in
   addition to glutamate (glycine or D-serine);
3. NMDA receptors possess a binding site for Mg2+
   within the ion pore;
   - Mg2+ block must be expelled by change in polarity before
   NMDA receptor pore can open.
4. NMDA receptors also possess binding sites for
   PCP, ketamine, memantine, MK-801, alcohol,
   benzodiazepines, barbiturates, etc

Question 18

NMDA is a coincidence detector
 only activates when

Answer 18

two
events occur close together in
time.
1. Glutamate released onto NMDA;
2. Cell membrane is depolarized

Question 19

n addition to the 3 ionotropic receptors, glutamate
also has ….. metabotropic receptors

Answer 19

8

Question 20

Long-term potentiation is mediated by activity of the

Answer 20

NMDA receptors

Question 21

Long-term potentiation (LTP) is defined as

Answer 21

• A persistent (>1 hour) increase in synaptic strength produced by a burst of
  activity in the presynaptic neuron;
• Initiated by a burst of firing activity (100 stimuli in ~1s) called tetanus;
• Synaptic enhancements produced by the tetanus is measured in EPSPs on
  the post-synaptic cell;

Question 22

There are many varieties of LTP

Answer 22

• Time period of potentiation (E- vs. L-LTP);
• Pre-synaptic vs. post-synaptic;
• Structural vs. biochemical modifications (or both);
• Underlying cellular mechanism.

Question 23

LTP occurs in many brain regions but was
first discovered in the

Answer 23

hippocampus

Question 24

The hippocampus is divided into three
principle pathways:

Answer 24

• Perforant path: entorhinal cortex  granule
  cells;
• Mossy fibers: granule cells  pyramidal cells
  in CA3;
• Schaffer collateral: CA3  CA1 (main
  pathway in LTP

Question 25

Glutamate binds to both .......receptor

Answer 25

AMPA & NMDA

Question 26

Once Ca2+ enters the cell via NMDA receptors, it alters the postsynaptic neuron by:

Answer 26

1. Increasing responsiveness of AMPA receptors to glutamate (how?); 2. Increase the number of AMPA receptors expressed on the post-synaptic membrane; 3. Triggers the release of retrograde messengers that cause more glutamate to be released from presynaptic neuron.

Question 27

Blocking NMDA receptors, particularly in the hippocampus, can interrupt the formation of

Answer 27

spatial memories

Question 28

Excitotoxicity can occur with overexposure to glutamate caused by a prolonged depolarization of the

Answer 28

postsynaptic neuron

Question 29

When both NMDA and non-NMDA receptors are subjected to prolonged stimulation by glutamate, a large % of cells die via 1 of 2 mechanisms:

Answer 29

necrosis and apoptosis

Question 30

necrosis and apoptosis

Answer 30

1. Necrosis: characterized by rapid lysis of the cell due to osmotic swelling; 2. Apoptosis: delayed cascade of biochemical events that leads to DNA breakup and ultimately cell death

Question 31

GABA is synthesized in

Answer 31

GABAergic neurons,

Question 32

GABA is made from glutamate, a reaction that is catalyzed by the enzyme

Answer 32

glutamic acid decarboxylase (GAD).

Question 33

The vitamin B6 derivative pyridoxal phosphate is a cofactor in the synthesis of

Answer 33

GABA

Question 34

Labeling of GAD in presynaptic nerve terminals shows us that GABA synthesis is localized with

Answer 34

mitochondria

Question 35

Following synthesis in the nerve terminals, GABA is stored in vesicles via

Answer 35

vesicular GABA transporters (VGAT)

Question 36

VGATs are also capable of transporting glycine into vesicles and are therefore also known as

Answer 36

vesicular inhibitory amino acid transporters (VIAAT)

Question 37

GABA is removed from the synaptic cleft by three different transporters:

Answer 37

GAT- 1, GAT-2 & GAT-3

Question 38

Once recycled, GABA is then metabolized back to glutamate and succinate by

Answer 38

GABA aminotransferase (GABA-T

Question 39

The best characterized binding site is the

Answer 39

benzodiazepine site (BzR

Question 40

Prototypical GABAA receptors are:

Answer 40

Selectively activated by muscimol: - Found in Fly Agaric mushrooms (and others); - Eaten for its stimulatory and hallucinogenic effects. Antagonized competitively by bicuculline: - Blocks binding of GABA to GABAA; - Potent convulsant. Antagonized non-competitively by picrotoxin. - Acts as a stimulant and convulsant; - Can cause respiratory paralysis.

Question 41

Because the GABAA receptor has multiple binding sites, the activity at the receptor can be exacerbated by

Answer 41

multiple ligands binding

Question 42

The action of alcohol, benzodiazepines (BDZs) and barbiturates potentiate the effects of

Answer 42

GABA on the GABAA receptor

Question 43

Barbiturates:

Answer 43

- E.g. Pentobarbital; - Increase the mean duration of opening time; - Increase the mean number of openings per burs

Question 44

Benzodiazepines

Answer 44

- E.g. Valium - Increase the open frequency of GABAA (BDZ agonis

Question 45

Picrotoxin

Answer 45

- Does not directly interact with binding site for barbiturates, but produces the opposite effects on the receptor; - Reduces the mean number of openings per burst; - Shortens the mean opening time;

Question 46

Barbiturates are a unique ligand for the GABAA receptor, as they exhibit three modes of action, depending on the concentration

Answer 46

1. At low concentrations, barbiturates act allosterically on the GABA-gated Cl- influx  co-agonist; 2. At higher concentrations, barbiturates open GABAA receptor channel directly, independent of the presence of GABA  agonist; 3. At very high concentrations, barbiturates block the Cl- current  antagonis