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Developmentally regulated neurosteroid synthesis enhances GABAergic neurotransmission in mouse thalamocortical neurones
Author(s) -
Brown Adam R.,
Herd Murray B.,
Belelli Delia,
Lambert Jeremy J.
Publication year - 2014
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2014.280263
Subject(s) - neuroactive steroid , neuroscience , inhibitory postsynaptic potential , gabaa receptor , gabaergic , thalamus , neurotransmission , postsynaptic potential , allopregnanolone , biology , receptor , chemistry , biochemistry
Key points During neuronal development synaptic events mediated by GABA A 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 GABA A 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 GABA A receptors, respectively, in physiological and pathophysiological scenarios associated with perturbed neurosteroid levels. Our data establish a potent, endogenous mechanism to locally regulate the GABA A receptor function and thereby influence thalamocortical activity.Abstract During brain development the duration of miniature inhibitory postsynaptic currents (mIPSCs) mediated by GABA A receptors (GABA A Rs) progressively reduces, to accommodate the temporal demands required for precise network activity. Conventionally, this synaptic plasticity results from GABA A R subunit reorganisation. In particular, in certain developing neurones synaptic α2‐GABA A Rs are replaced by α1‐GABA A 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 GABA A 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 GABA A 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 GABA A R‐inactive precursor 5α‐dihydroprogesterone (5α‐DHP) resulted in markedly prolonged mIPSCs and a greatly enhanced tonic conductance, mediated by synaptic and extrasynaptic GABA A 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.