Neurosteroid modulation of benzodiazepine-sensitive GABAA tonic inhibition in supraoptic magnocellular neurons

Ji Yoon Jo, Ji Ae Jeong, Sudip Pandit, Javier Eduardo Stern, Seul Ki Lee, Pan Dong Ryu, So Yeong Lee, Seong Kyu Han, Chung Hyun Cho, Hyun Woo Kim, Byeong Hwa Jeon, Jin Bong Park

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Interactions between neurosteroids and GABA receptors have attracted particular attention in the supraoptic nucleus (SON). Although GABAa receptors (GABAaR) mediate a sustained tonic inhibitory current (Itonic), as well as conventional phasic inhibitory postsynaptic currents (IPSCs, Iphasic) in the SON, whether the steroid modulation on Itonic is present in SON magnocelluar neurosecretory cells (MNCs) is unknown. Here, we addressed this question and gained insights into the potential molecular configuration of GABAA receptors mediating Itonic and conferring its neurosteroids sensitivity in SON MNCs. 4,5,6,7-tetra-hydroisoxazolo[5,4-c]-pyridin-3-ol (THIP) (1 μM, a relatively selective extrasynaptic GABAaR agonist, facilitated Itonic without affecting the main characteristics of IPSCs, while DS-2, a relatively selective modulator of GABAaR δ-subunits, caused minimal changes in Itonic of SON MNCs. L-655,708, a relatively selective GABAaR ct5-subunit inverse agonist, blocked ~35% of the total Itonic both under basal and elevated ambient GABA concentration (3 (μM). Facilitation of Itonic by benzodiazepines further supported the role of GABAaR 72-subunit in Itonic of SON MNCs. Quantitative RT-PCR analysis showed much lesser expression of GABAaR 8-subunit than the α5 or γ-subunit in the SON. Allopregnanolone and 3α,5α-tetrahydrodeoxycorticosterone increased both Itonic and Iphasic in SON MNCs, respectively, although more than 90% of the current increase was mediated by Itonic during the neurosteroid facilitation. Finally, L-655,708 attenuated the neurosteroid facilitation of Itonic but not of Iphasic. Altogether, our results suggest that Itonic, mediated mainly by benzodiazepine-sensitive GABAaRs containing α5-β, γ2 and to a lesser extent, δ-subunits, is a potential target of neurosteroid modulation in SON neurons.

Original languageEnglish (US)
Pages (from-to)1578-1587
Number of pages10
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume300
Issue number6
DOIs
StatePublished - Jun 2011

Keywords

  • Extrasynaptic
  • Gabaa receptors
  • Neurosteroid
  • Oxytocin
  • Vasopressin

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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    Jo, J. Y., Jeong, J. A., Pandit, S., Stern, J. E., Lee, S. K., Ryu, P. D., Lee, S. Y., Han, S. K., Cho, C. H., Kim, H. W., Jeon, B. H., & Park, J. B. (2011). Neurosteroid modulation of benzodiazepine-sensitive GABAA tonic inhibition in supraoptic magnocellular neurons. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 300(6), 1578-1587. https://doi.org/10.1152/ajpregu.00627.2010