Phosphorylation influences neurosteroid modulation of synaptic GABAA receptors in rat CA1 and dentate gyrus neurones

The neurosteroid 5beta-pregnan-3alpha-ol-20-one (5beta3alpha) is a potent, endogenous, positive allosteric modulator of the GABA(A) receptor. Relatively low concentrations of 5beta3alpha (10-100 nM), thought to occur physiologically, caused a concentration-dependent slowing of the decay of GABA-mediated miniature inhibitory postsynaptic currents (mIPSCs) recorded from hippocampal CA1 pyramidal neurotics. However, much greater concentrations of this neurosteroid (greater than or equal to300 nM) were required to similarly influence dentate granule cell mIPSCs. By contrast, the allosteric modulators pentobarbitone and flunitrazepam were equi-effective in prolonging mIPSCs in both neuronal types. Hence, the neurosteroid selectively differentiates between the synaptic GABA(A) receptors of these hippocampal neurotics. Inhibition of either protein kinase A, or C, greatly reduced the sensitivity of CA1 synaptic GABA(A), receptors to 5beta3alpha, but not pentobarbitone. whereas stimulation of PKC had no effect on steroid sensitivity. However, in dentate gyrus granule cells, activation of PKC made mIPSCs sensitive to a previously ineffective concentration of 5beta3alpha. Collectively, these results Suggest that the GABA-modulatory effects of physiological levels of the neurosteroid will not be uniformly experienced throughout the central nervous system. or even,within the same brain region such as the hippocampus, but will be neurone-specific and will be dependent on the phosphorylation status of the GABA(A) receptor, or associated proteins. (C) 2003 Elsevier Ltd. All rights reserved.