title: Modulation of allopregnanolone on excitatory transmitters release from single glutamatergic terminal.
abstract: Neurosteroids such as allopregnanolone (Allo) are widely distributed in the brain and may modulate neuronal excitability under physiological or pathological states. Allo modulates GABAA receptor responses, and in this study we investigated the functional effects of Allo on presynaptic GABAA receptors on single glutamatergic nerve terminal projecting on CA3 neurons. In the present study, we measured spontaneous and evoked excitatory postsynaptic currents (sEPSCs and eEPSCs), the latter was elicited with single or paired-pulse focal electrical stimulation, using mechanically isolated 'synaptic bouton' preparation. Allo (10 nM) increased significantly eEPSC amplitude while decreasing the failure rate (Rf) and the paired-pulse response ratio (PPR). Conversely high concentration (100 nM) of Allo decreased eEPSC amplitude and increased Rf and PPR. Allo also increased significantly the frequency and amplitude of sEPSCs at low concentrations (10-30 nM) but at high concentration (100 nM) it had no effect on current amplitude but modestly decreased sEPSC frequency. Application of Allo at nanomolar concentrations facilitated exogenous muscimol-induced outward postsynaptic currents but had no effect on glutamate-induced inward postsynaptic currents. Our results demonstrate that Allo modulates glutamate release via presynaptic GABAA receptors, in addition to its better characterized effects to modulate postsynaptic GABAA responses. Both pre- and postsynaptic GABAA receptor modulation is likely to contribute to the physiological actions of neurosteroids.
authors.affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Iwata
authors.forename: Masahito
authors.initials: M
authors.lastname: Wakita
authors.forename: Min-Chul
authors.initials: MC
authors.lastname: Shin
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
authors.forename: Norio
authors.initials: N
authors.lastname: Akaike
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D001703:Biophysics; D056547:CA1 Region, Hippocampal / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D009118:Muscimol / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects*; D019789:Tetraethylammonium / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D026902:Potassium Channel Blockers; D009118:Muscimol; D018698:Glutamic Acid; D019789:Tetraethylammonium; C056639:2-amino-5-phosphopentanoic acid; D011280:Pregnanolone; D014633:Valine; D001640:Bicuculline