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Neurosteroid Modulation of Synaptic and Extrasynaptic GABA Receptors of the Mouse Nucleus Accumbens. | LitMetric

AI Article Synopsis

  • Recent approvals of the neurosteroids allopregnanolone (brexanolone) and SAGE-217 (zuranolone) for postpartum depression (PPD) have sparked further research into their effects on GABA receptors (GABARs) in the brain.
  • Studies show that individuals with PPD exhibit reduced activity in the brain's reward pathways, and this may be linked to how neurosteroids influence GABAergic transmission in the nucleus accumbens.
  • The research indicates that neurosteroids enhance tonic inhibition in medium spiny neurons through their interaction with GABARs and suggests that fluctuations in allopregnanolone levels during and after pregnancy could affect GABAergic functions.*

Article Abstract

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABAR function are clinically effective in this condition. Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens are associated with reward/motivation and brain imaging studies report that individuals with PPD show reduced activity of this pathway in response to reward and infant engagement. However, the influence of neurosteroids on GABA-ergic transmission in the nucleus accumbens has received limited attention. Here, we investigate, in the medium spiny neurons (MSNs) of the mouse nucleus accumbens core, the effect of allopregnanolone, SAGE-217 and other endogenous and synthetic steroids of interest on fast phasic and tonic inhibition mediated by synaptic (α1/2βγ2) and extrasynaptic (α4βδ) GABARs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABARs, where the steroid-enhanced tonic current is GABA-dependent. Furthermore, we demonstrate local neurosteroid synthesis in the accumbal slice preparation and reveal that GABA-ergic neurotransmission of MSNs is influenced by an endogenous neurosteroid tone. Given the dramatic fluctuations in allopregnanolone levels during pregnancy and postpartum, this neurosteroid-mediated local fine-tuning of GABAergic transmission in the MSNs will probably be perturbed.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11048561PMC
http://dx.doi.org/10.3390/biom14040460DOI Listing

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