title: Developmentally regulated neurosteroid synthesis enhances GABAergic neurotransmission in mouse thalamocortical neurones.
abstract: During neuronal development synaptic events mediated by GABAA receptors are progressively reduced in their duration, allowing for rapid and precise network function. Here we focused on ventrobasal thalamocortical neurones, which contribute to behaviourally relevant oscillations between thalamus and cortex. We demonstrate that the developmental decrease in the duration of inhibitory phasic events results predominantly from a precisely timed loss of locally produced neurosteroids, which act as positive allosteric modulators of the GABAA receptor. The mature thalamus retains the ability to synthesise neurosteroids, thus preserving the capacity to enhance both phasic and tonic inhibition, mediated by synaptic and extrasynaptic GABAA receptors, respectively, in physiological and pathophysiological scenarios associated with perturbed neurosteroid levels. Our data establish a potent, endogenous mechanism to locally regulate the GABAA receptor function and thereby influence thalamocortical activity. During brain development the duration of miniature inhibitory postsynaptic currents (mIPSCs) mediated by GABAA receptors (GABAA Rs) progressively reduces, to accommodate the temporal demands required for precise network activity. Conventionally, this synaptic plasticity results from GABAA R subunit reorganisation. In particular, in certain developing neurones synaptic α2-GABAA Rs are replaced by α1-GABAA Rs. However, in thalamocortical neurones of the mouse ventrobasal (VB) thalamus, the major alteration to mIPSC kinetics occurs on postnatal (P) day 10, some days prior to the GABAA R isoform change. Here, whole-cell voltage-clamp recordings from VB neurones of mouse thalamic slices revealed that early in postnatal development (P7-P8), the mIPSC duration is prolonged by local neurosteroids acting in a paracrine or autocrine manner to enhance GABAA R function. However, by P10, this neurosteroid 'tone' rapidly dissipates, thereby producing brief mIPSCs. This plasticity results from a lack of steroid substrate as pre-treatment of mature thalamic slices (P20-24) with the GABAA R-inactive precursor 5α-dihydroprogesterone (5α-DHP) resulted in markedly prolonged mIPSCs and a greatly enhanced tonic conductance, mediated by synaptic and extrasynaptic GABAA Rs, respectively. In summary, endogenous neurosteroids profoundly influence GABAergic neurotransmission in developing VB neurones and govern a transition from slow to fast phasic synaptic events. Furthermore, the retained capacity for steroidogenesis in the mature thalamus raises the prospect that certain physiological or pathophysiological conditions may trigger neurosteroid neosynthesis, thereby providing a local mechanism for fine-tuning neuronal excitability.
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee, DD1 9SY, UK.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Brown
authors.forename: Murray B
authors.initials: MB
authors.lastname: Herd
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
mesh_terms: D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / Q000494:pharmacology; D043582:5-alpha-Dihydroprogesterone / Q000494:pharmacology; D000375:Aging / Q000502:physiology; D000818:Animals; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D011280:Pregnanolone / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D013788:Thalamus / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D043582:5-alpha-Dihydroprogesterone; D011280:Pregnanolone; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)