10 Amino Acids: Glutamate & GABA

Question 1

How are glutamate and GABA neurons distributed throughout the brain?

Answer 1

Unlike NTs such as DA and 5-HT which have discrete areas of the brain where they are made and cells which project broadly throughout the brain, glutamate and GABA neurons are broadly distributed - don’t have specific nuclei

Question 2

What is the most abundant excitatory NT in the brain?

Answer 2

Glutamate

Question 3

What does glutamate do?

Answer 3

Involved in learning, neural plasticity, memory and dark exposure. Also involved in excitotoxicity following stroke or ischemia.

Question 4

What are some glutamate ant/agonists?

Answer 4

Agonists - NMDA, AMPA, kainate, ibotenate.

Antagonists - AP5, ketamine, PCP, MK-801

Question 5

Why are NMDA and AMPA compounds and receptors?

Answer 5

Because these artificial compounds were first used to isolate types of receptors, which are now called NMDA and AMPA receptors

Question 6

How does glutamate activate ionotropic NMDA and AMPA receptors?

Answer 6

AMPA receptors open as soon as glutamate binds to them -> depolarisation

NMDA receptors are usually blocked by Mg2+ ion. Slight increase in cell voltage, as well as presence of ligand, is needed for ion channel to open.

NMDA and AMPA (non-NMDA) receptors are often found together - AMPA receptors cause increase in cell voltage needed for NMDA receptors to open

Question 7

Are all glutamate receptors ionotropic?

Answer 7

No, many are metabotropic, such as mGluR2/3, mGluR1/5 etc.

Question 8

What is long-term potentiation (LTP)?

Answer 8

A long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously

Question 9

What is tetanus?

Answer 9

The prolonged contraction of a muscle caused by rapidly repeated stimuli. Or in neuroscience, rapidly repeated stimulation of neuron. May be one way that synaptic strength can be modified by experience to produce learning and lasting memories

Question 10

How was LTP discovered?

Answer 10

It was found that postsynaptic cells’ response to single-pulse stimuli could be enhanced for a long period of time if a high-frequency train of stimuli (tetanus) was first delivered to the presynaptic fibers. When such a train of stimuli was applied, subsequent single-pulse stimuli elicited stronger, prolonged EPSPs in the postsynaptic cell population. This phenomenon, whereby a high-frequency stimulus could produce a long-lived enhancement in the postsynaptic cells’ response to subsequent single-pulse stimuli, was eventually called LTP.

Question 11

How does LTP explain classical conditioning?

Answer 11

In classical conditioning experiment, initial weak stimulus could be a bell; tetanus could be presentation of food or other biologically significant event. When these two things happen together, the weak stimulus can produce a greater response -> CS-CR association

Question 12

What causes LTP induction at the cell level?

Answer 12

More NT release and more NT receptors.
When cell is subjected to tetanus, increased calcium concentration in the cell, which leads to insertion of more AMPA receptors in postsynaptic neuron. So next time presynaptic cell is stimulated, there are more receptors to respond to NT release.

Question 13

Which NT is most involved in LTP?

Answer 13

Glutamate

Question 14

How has it been demonstrated neurochemically that NMDA receptors are involved in LTP?

Answer 14

NMDA receptor antagonists block LTP

Question 15

Which part of the brain has LTP been shown to happen?

Answer 15

Primarily in the hippocampus and neocortex - the parts of the brain associated with learning

Question 16

How can the Morris Water Maze be used to test glutamate’s role in learning?

Answer 16

If rats given glutamate antagonist AP5 during learning phase of Morris Water Maze, they show no preference for particular quadrant in test phase –they don’t know where the platform is. No evidence for learning; swim as if on first time.

Question 17

What does the AMPA/NMDA ratio test?

Answer 17

There are more AMPA receptors after LTP, so it is a way of testing whether LTP has occurred.

Question 18

How does cocaine affect AMPA/NMDA ratio?

Answer 18

People in cocaine withdrawal have increased AMPA/NMDA ratio. This is one possible cause for cocaine sensitization effect.

Question 19

What is the most abundant inhibitory NT in the brain?

Answer 19

GABA

Question 20

Why is GABA inhibition important?

Answer 20

Brain wouldn’t work if everything was active all the time. Must turn things off to get clear signal. Like muscles - antagonist pairs, must relax one muscle to tense other. If you tense all -> no action.

Question 21

What are the two functional types of neurons of the cerebral cortex?

Answer 21

Principal (projection) neurons and interneurons

Question 22

What are projection neurons?

Answer 22

The most numerous group of cortical neuron (approximately 80%), projection neurons send their axons to distant targets in the brain. They are excitatory in their influence on other cells and are characterized morphologically by having small spines on their dendritic surfaces that act as specialized sites for synaptic contact. A projection neuron typically has about 10,000 synapses on its dendritic tree; also, its axon may have a number of collateral branches, almost always using the excitatory neurotransmitter glutamate.

Question 23

What are interneurons?

Answer 23

Interneurons have short axons and make connections to cells in their immediate vicinity. The less numerous (20%) group of cortical neurons, the interneurons, are generally stellate in morphology, but largely lack dendritic spines, contain GABA as their synaptic transmitter and are inhibitory in their output to other cells. Interneurons, which are of many subtypes, connect projection neurons, providing mostly logical functions via the inhibitory neurotransmitter GABA. They control baseline activity rates, signal-to-noise ratios etc.

Question 24

What are some GABA agonists?

Answer 24

Benzodiazepines, barbituates, alcohol

Question 25

How do GABA-A receptors work?

Answer 25

GABA-A receptors are ionotropic and contain a Cl- channel. This channel opens when an agonist binds to the receptor and conducts Cl- to hyperpolarize the cell (i.e. decrease voltage making it less likely to fire)

Question 26

What binding sites to GABA-A receptors have?

Answer 26

GABA-A receptors have binding sites for benzodiazepines and barbiturates

Question 27

How do GABA-B receptors work?

Answer 27

GABA-B receptors are metabotropic transmembrane receptors for GABA, linked via G-proteins to a potassium channel. The opening of a K+ channel also hyperpolarizes the cell - positive ions flow OUT of the cell.

Question 28

Where are GABA-B receptors found?

Answer 28

Both pre- and post-synaptically, so they can inhibit NT release in addition to hyperpolarizing the postsynaptic cell

Question 29

What are the properties of benzodiazepines?

Answer 29

Anxiolytic, muscle relaxant, hypnotic/sedative, anticonvulsant, amnesic, ataxic

Question 30

What is ataxia?

Answer 30

Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum.

Question 31

How can GABA agonists influence seizures?

Answer 31

Seizures are excessive unregulated neural activity - may include motor manifestations (convulsions). GABA inhibits brain activity, reduces severity of seizure.

Question 32

What is an experimental use of GABA agonists?

Answer 32

Drugs such as Muscimol - GABA-A receptor agonist - are commonly used to experimentally inactivate specific brain regions. Chemical lesioning.