Neurobiology, lecture on Neurosteroids
XXX. Neurosteroids
A. Steroids are accumulated in the brain & produced de novo
1. Peripheral F/B, P, T, E2 have receptors in specific brain regions
a. steroid concentrating neurons
2. converting enzymes like P450aro (= aromatase, T ® E2) also
B. de novo and metabolic Brain Steroidogenesis
1. pregnenolone, DHEA, 5aDHP,
allopregnanolone=3a5aTHP, THDOC
a. P450scc, 3b-HSD, 5a-reductase, 3a-oxidoreductase
present centrally in glia
C. Peripheral steroids bind to classical cytoplasmic/nuclear receptors
to activate genomic actions
1. especially immediate-early genes with products important
for neurochemical and endocrine function
a. code for G-proteins, receptors,
protein kinases, transcription factors...
D. Non-genomic actions
1. de novo central neurosteroids bind to
ionotropic receptors, especially GABAA
a. ligand-gated channels for ions (Cl-, Ca++)
2. allosteric modulators of ion influx
a. ionotropic receptors have multiple membrane
spanning subunits (usually 5) with more
than one ligand binding site
i. unique binding site for steroids
3. positive allosteric modulators of GABAA Cl- influx
a. THP = allopregnanolone
b. THDOC = tetrahydrodeoxycorticosterone
i. less potent: androsterone (from DHEA)
c. result: neuronal inhibition
i. reversible structural regression in hippocampus
ii. ratio between excitatory & inhibitory
steroids shape synaptic activity
d. effects: anxiolytic, antiaggressive,
anesthetic, sedative, hypnotic
i. blunted reaction to stimuli
(1) antisocial behavior, inclination to substance abuse?
4. negative allosteric modulators of GABAA Cl- influx
a. Preg-S = pregnenolone sulfate
i. less potent : Preg
b. DHEAS = dehydroepiandrosterone sulfate
i. less potent: DHEA, androstenedione,
ii. binding site distinct from Preg-S,
close to barbiturate binding site
c. positively modulate NMDAGlu-R Ca++ influx
i. excitatory steroids
d. effects: enhance neuronal and glial survival &
structural growth, neuronal differentiation,
neuroprotective, enhance memory, anxiety,
basal CNS arousal convulsions, seizures,
sedation threshold
i. positive correlations with longevity, vigor,
resistance to cancer and cardiovascular diseases
5. specific G-protein mediated receptors have been
discovered for B, P & E2
E. may alter neuro-microanatomy
1. B reduces the number of dendritic spines
on hippocampal pyramidal cells
2. E2 and 5aDHP increase dendritic
spines on hippocampal pyramidal cells
F. affect behavior
1. E2 increases and B decreases capacity for memory