During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons

As neuronal development progresses, GABAergic synaptic transmission undergoes a defined program of reconfiguration. For example, GABA(A) receptor (GABA(A)R)-mediated synaptic currents, (miniature inhibitory postsynaptic currents; mIPSCs), which initially exhibit a relatively slow decay phase, become progressively reduced in duration, thereby supporting the temporal resolution required for mature network activity. Here we report that during postnatal development of cortical layer 2/3 pyramidal neurons, GABA(A)R-mediated phasic inhibition is influenced by a resident neurosteroid tone, which wanes in the second postnatal week, resulting in the brief phasic events characteristic of mature neuronal signalling. Treatment of cortical slices with the immediate precursor of 5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha), the GABA(A)R-inactive 5 alpha-dihydroprogesterone, (5 alpha-DHP), greatly prolonged the mIPSCs of P20 pyramidal neurons, demonstrating these more mature neurons retain the capacity to synthesize GABA(A)R-active neurosteroids, but now lack the endogenous steroid substrate. Previously, such developmental plasticity of phasic inhibition was ascribed to the expression of synaptic GABA(A)Rs incorporating the alpha 1 subunit. However, the duration of mIPSCs recorded from L2/3 cortical neurons derived from alpha 1 subunit deleted mice, were similarly under the developmental influence of a neurosteroid tone. In addition to principal cells, synaptic GABA(A)Rs of L2/3 interneurons were modulated by native neurosteroids in a development dependent manner. In summary, local neurosteroids influence synaptic transmission during a crucial period of cortical neurodevelopment, findings which may be of importance for establishing normal network connectivity. (C) 2015 The Authors. Published by Elsevier Ltd.