Lecture 25 - GABAergic Signalling in Health and Disease

Question 1

What is GABA?

Answer 1

Gamma-aminobutryic acid.

Question 2

What is the function of GABA?

Answer 2

Primary inhibitory NT in the CNS.
Widely distributed throughout the CNS.
Present at high concentrations in the brain, retina and spinal cord.

Question 3

What are the 2 types of GABA receptors?

Answer 3

Ionotropic - GABAa, GABAc ligand-gated ion channels, both linked to a chloride channel.
Metabotropic - GABAb G-protein coupled receptors.

Question 4

What are GABAa responses mediated by?

Answer 4

Chloride current across the neuronal membrane.

Question 5

What happens when membrane potential in a cell changes?

Answer 5

There is a passive flux of Cl- out of and into the cell.
In certain conditions, GABAa responses can be depolarising, sometime excitatory - early in development and in some phases of circadian rhythm, trauma and epilepsy.

Question 6

What is EGABA?

Answer 6

GABA reversal potential (when GABA response change polarity, dependent on chloride conc).

Question 7

What does a primary active transporter rely on?

Answer 7

Metabolic energy (ATP).
Sodium out, potassium in requires energy.

Question 8

Where does a secondary active transporter get its energy from?

Answer 8

Ionic concentration differences in sodium and potassium across the membrane.

Question 9

What are changes in EGABA mediated by?

Answer 9

Secondary active transporters that either take up or extrude Cl-.

Question 10

What is Cl- uptake mediated by?

Answer 10

Na+-K+-2Cl- co transporters, Na+ independent anion exchangers.

Question 11

What is Cl- extrusion mediated by?

Answer 11

K+Cl- co transporters, Na+ dependent anion exchangers.

Question 12

What are cation chloride co-transporters?

Answer 12

Large transmembrane glycoproteins.

Question 13

Where is the cation chloride co-transporter, NKCC1 prominently expressed?

Answer 13

CNS

Question 14

Where is the cation chloride co-transporter, KCC2 expressed?

Answer 14

Mature neurons and is responsible for low [Cl-] in mature cells.

Question 15

When are GABAa responses depolarising?

Answer 15

When they elicit a chloride efflux.
Happens when the chloride extrusion from the cell is weaker (less KCC2 action) or when chloride uptake by the cell is stronger (NKCC1 activity is increased).

Question 16

Describe GABAa receptor activation during embryonic and neonatal development.

Answer 16

EGABA is more positive than V rest in early development so GABA depolarises developing neocortical cells.
EGABA is the most positive in youngest precursor cells.
Progressively shifts to more negative values with development, determined by the Cl- gradient.
Chloride concentration decreases with development.

Question 17

What happens if GABAa responses remain excitatory?

Answer 17

Prevents the generation of the synchronous motor activity.

Question 18

Why does GABAa maturation occur earlier in females?

Answer 18

Females predominant sex hormone is oestrogen and oestrogen unregulated KCC2 mrRNA via GABA receptors and calcium channels.
Whereas, in males their predominant sex hormone is testosterone that down regulates KCC2 mRNA via GABA receptors and calcium channels.

Question 19

What protects foetal neurons during birth?

Answer 19

Depolarising GABA effect transiently decreases around birth, mediated by oxytocin.
Oxytocin lowers chloride concentration through a NKCC1 blockade, decreasing foetal brain resistance to anoxia-glycaemia at birth protecting their neurons.

Question 20

Describe GABA in the SCN.

Answer 20

SCN neurons are pacemakers and most are GABAergic.
Changes in GABAa activity throughout the circadian clock influence the SCN output during the day and night (different gating mechanism).
Inhibitory during the day, excitatory during the night.