Neurosteroids

Question 1

How do neurosteroids cause changes in the genome?

Answer 1

Either diffuse via interstitial space or through the plasma membrane of the target cell
Bind to the receptor complex in the nucleus
This attaches to a target site on the DNA strand
There is activation of transcription of a specific gene

Question 2

How long does the onset and offset of non-genomic actions of neurosteroids take?

Answer 2

Onset - rapid, seconds/minutes

Offset - short duration of action following the clearance from tissue

Question 3

How long does the onset and offset of genomic actions of neurosteroids take?

Answer 3

Slower in onset - minutes/hours

Longer duration of action after the steroid is cleared from the tissue

Question 4

What is the structure of alphaloxone structurally similar to?

Answer 4

Naturally occurring steroids

Question 5

Where does alphaxalone act?

Answer 5

On a separate binding site on the GABAa receptors `

Question 6

What is the main action of alphaxalone?

Answer 6

PAM at GABAa receptors

Question 7

What is seen on administration of alphaxalone to a cuneta brain slice?

Answer 7

Dose dependent depolarisations

Question 8

What is the activity of the isomer of alphaxalone, betaxalone?

Answer 8

None

Question 9

Why is it probably that alphaxalone acts outwith classical intracellular steroid receptors?

Answer 9

Radioligand binding experiments involve only the synaptic membranes
There are no intracellular steroid receptors present
But a positive response is observed

Question 10

Which common substances increases neurosteroid levels?

Answer 10

Alcohol

Prozac

Question 11

In which physiological state do levels of neurosteroids increase?

Answer 11

Labour
Stress
Increase greatly before and during labour
Plummet during and after

Question 12

Why is it thought that neurosteroid levels increase rapidly at labour?

Answer 12

Anxiolytic, anticonvulsant and sedative

Question 13

How do neurosteroids enhance tonic inhibition?

Answer 13

Increase the probability of GABA receptors staying open

Leads to increased inhibition signalling

Question 14

Where do neurosteroids act to keep stress levels down?

Answer 14

CRH-releasing paraventricular neurons

(This prevents further release of stress hormones)

Gunn 2013

Question 15

What may increase CRF expression?

Answer 15

ELS

Gunn 2013

Question 16

How does ELS affect neurosteroid function?

Answer 16

Increases CRF function so there is more work needed to inhibit

Prevents the inhibition though but increase in glutamate release

Gunn 2013

Question 17

Which species have neurosteroid-insensitive GABAa receptors?

Answer 17

Invertebrates

Drosphilia

Question 18

How do we know that drosophilia are neursteroid insensitive?

Answer 18

At high dose, where the GABA response increases approx. 6 fold in humans

The effect is minimal in the drosophilia
Flies with relatively no effect

Question 19

How do the human and drosphilia GABA a receptor differ?

Answer 19

In the first transmembrane region
At place 241, there is a W in the fly instead of a Q (which there is in humans)

Hosie et al 2006

Question 20

How do we know that difference at position 241 between human and fly is relevant to GABA?

Answer 20

alpha-2 Q241W mice have an anxiogenic phenotype
Demonstrated in results of light-dark box and EPM

Also GABA mediated IPSCs in NAc with reduced even without neurosteroid application

Question 21

What locally modulates GABA activation?

Answer 21

Local cells production of steroids

Question 22

Why does the duration of GABA channel opening change in post-natal development?

Answer 22

Need more precise opening/closing of channels

To get more specific GABAaR mediated phasic inhibition

Question 23

How is the duration of GABAaR opening changed during post natal development?

Answer 23

Subunit composition is altered

Question 24

Which subunit is associated with faster open/close of the GABA channels?

Answer 24

alpha 1

alpha 2 is slower

Question 25

How do we think that alpha 1 is a/w faster opening/closing times?

Answer 25

Induced overexpression of alpha1 subunit in mice lead to events occurring faster

Okada et al 2000

Question 26

Why is it possible that subunit composition changes is not/not wholly responsible for changes in transmission speed?

Answer 26

At p10, there are lots of a2 receptors but there is still fast transmission
So alpha1 cant be the only reason

Also in alpha 1 KO mice, there is the same increase in transmission rate

Question 27

Why is it possible that neurosteroids are actually the reason that the duration of channel opening changes?

Answer 27

Finasteride from alpha-5 reductase which is needed to form the GABA steroids
This reduced the duration of VB neuron action

Also, GABAaRs remain neurosteroid sensitive, just have less activity. Implies less neurosteroids is the cause

Brown et al 2015

Question 28

Activation of which receptor increases neurosteroid activation in hippocampal neurons?

Answer 28

NMDAR

Tokuda et al 2011

Question 29

How do Tokuda et al 2011 show that NMDAR activation increases neurosteroid production?

Answer 29

Cultured hippocampal neuron
Stained with an Ab for neurosteroids
Added NMDA
There was then increased fluorescence

Question 30

Why may increase in excitatory receptors cause increase in neurosteroids which act on GABAaR?

Answer 30

To correct the E/I balance

Question 31

Which drug has just been approved for post partum depression?

Answer 31

Brexanolone

Question 32

Why may targeting neurosteroids help with post partum depression?

Answer 32

The sudden drop in neurosteroids may be the cause of ppd
But the GABAaR expression takes longer to correct
This mismatch may be what causes PPD
Treatment with allopregnanolone seems to help
Mody 2019