Neurosteroids Flashcards
How do neurosteroids cause changes in the genome?
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
How long does the onset and offset of non-genomic actions of neurosteroids take?
Onset - rapid, seconds/minutes
Offset - short duration of action following the clearance from tissue
How long does the onset and offset of genomic actions of neurosteroids take?
Slower in onset - minutes/hours
Longer duration of action after the steroid is cleared from the tissue
What is the structure of alphaloxone structurally similar to?
Naturally occurring steroids
Where does alphaxalone act?
On a separate binding site on the GABAa receptors `
What is the main action of alphaxalone?
PAM at GABAa receptors
What is seen on administration of alphaxalone to a cuneta brain slice?
Dose dependent depolarisations
What is the activity of the isomer of alphaxalone, betaxalone?
None
Why is it probably that alphaxalone acts outwith classical intracellular steroid receptors?
Radioligand binding experiments involve only the synaptic membranes
There are no intracellular steroid receptors present
But a positive response is observed
Which common substances increases neurosteroid levels?
Alcohol
Prozac
In which physiological state do levels of neurosteroids increase?
Labour
Stress
Increase greatly before and during labour
Plummet during and after
Why is it thought that neurosteroid levels increase rapidly at labour?
Anxiolytic, anticonvulsant and sedative
How do neurosteroids enhance tonic inhibition?
Increase the probability of GABA receptors staying open
Leads to increased inhibition signalling
Where do neurosteroids act to keep stress levels down?
CRH-releasing paraventricular neurons
(This prevents further release of stress hormones)
Gunn 2013
What may increase CRF expression?
ELS
Gunn 2013
How does ELS affect neurosteroid function?
Increases CRF function so there is more work needed to inhibit
Prevents the inhibition though but increase in glutamate release
Gunn 2013
Which species have neurosteroid-insensitive GABAa receptors?
Invertebrates
Drosphilia
How do we know that drosophilia are neursteroid insensitive?
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
How do the human and drosphilia GABA a receptor differ?
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
How do we know that difference at position 241 between human and fly is relevant to GABA?
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
What locally modulates GABA activation?
Local cells production of steroids
Why does the duration of GABA channel opening change in post-natal development?
Need more precise opening/closing of channels
To get more specific GABAaR mediated phasic inhibition
How is the duration of GABAaR opening changed during post natal development?
Subunit composition is altered
Which subunit is associated with faster open/close of the GABA channels?
alpha 1
alpha 2 is slower
How do we think that alpha 1 is a/w faster opening/closing times?
Induced overexpression of alpha1 subunit in mice lead to events occurring faster
Okada et al 2000
Why is it possible that subunit composition changes is not/not wholly responsible for changes in transmission speed?
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
Why is it possible that neurosteroids are actually the reason that the duration of channel opening changes?
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
Activation of which receptor increases neurosteroid activation in hippocampal neurons?
NMDAR
Tokuda et al 2011
How do Tokuda et al 2011 show that NMDAR activation increases neurosteroid production?
Cultured hippocampal neuron
Stained with an Ab for neurosteroids
Added NMDA
There was then increased fluorescence
Why may increase in excitatory receptors cause increase in neurosteroids which act on GABAaR?
To correct the E/I balance
Which drug has just been approved for post partum depression?
Brexanolone
Why may targeting neurosteroids help with post partum depression?
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
