Neurosteroids

Question 1

How is 5alpha3alpha (allopregnanolone) made in the brain?

Answer 1

Cholesterol enters the mitochondria -> catalysed by CYP11A1 -> pregnenolone (leaves mitochondria) -> progesterone -> allopregnanolone

Can occur in glial cell or presynaptic terminal

Question 2

What was the experiment that discovered that Drosophila GABAARs are steroid-insensitive?

Answer 2

10^-6 M 5alpha3alpha elicited a max GABA response in humans, whereas it only just about spurred a reaction in Drosophila GABA, needing 10^-5 M for a max effect

Much more is needed for an effect in Drosophila

Question 3

How is 5alpha3alpha made from progesterone?

Answer 3

Progesterone -> 5alpha-DHP (by 5alpha-reductase)

5alpha-DHP -> 5alpha3alpha (by 3alpha-HSD)

Question 4

What experiment showed that early in development (P7) synaptic GABAARs of thalamic ventrobasal neurons are influenced by an endogenous neurosteroid tone?

Answer 4

Brown, 2015

Isolated thalamic brain slice
Measure mIPSCs
Adding 50 microM finasteride (blocks 5alpha-reductase - prevents synthesis of 5alpha3alpha from progesterone) -> mIPSC shortened

Question 5

What improvements could be made for neurosteroids?

Answer 5

• More suitable for oral delivery
• Reduced GABAAR efficacy (to limit sedation) (increasing is fine until it starts to cause sedation)
• Improved pharmacokinetics (such as with ganaxolone)