Intact Synaptic GABAergic Inhibition and Altered Neurosteroid Modulation of Thalamic Relay Neurons in Mice Lacking δ Subunit

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Abstract
Robust GABA-mediated inhibitory postsynaptic currents (IPSCs) in neurons of the thalamic relay (TC) nuclei are important in sustaining oscillatory activity within thalamic and thalamocortical circuits. The biophysical properties and pharmacological sensitivities of these IPSCs both depend on the subunit combination of postsynaptic γ-aminobutyric acid-A (GABAA) receptors. Recombinant GABAAreceptors containing the δ subunit (heavily expressed in TC nuclei) have been shown to exhibit slowed desensitization rates and high affinity for GABA in heterologous expression systems. We tested whether the GABAA-mediated synaptic inhibition in TC neurons would be affected by loss of the δ subunit. Spontaneous and evoked IPSCs were recorded from neurons in the ventral basal complex (VB) of the thalamus from brain slices of wild-type (δ+/+) and homozygous δ subunit deficient mice (δ−/−). Spontaneous IPSCs (sIPSCs) from δ−/−mice had no significant differences in amplitude, duration, or frequency compared with their δ+/+counterparts. However, baseline noise (63% of control) and the relative contribution of the slow component to overall decay (79% of control) were significantly lower in δ−/−VB recordings. Evoked IPSCs (eIPSCs) in δ−/−neurons showed no difference in peak amplitude, but had an accelerated slow decay component (40- vs. 55-ms time constant). We further tested whether neurosteroid modulation of GABAAreceptors was dependent on the presence of the δ subunit, as previously reported in recombinant systems. Pregnenolone sulfate (PS) significantly reduced eIPSC peak amplitude (−30%) and increased duration in δ−/−, but not in δ+/+mice. sIPSCs were not affected in any neurons, δ−/−or δ+/+. In contrast, 3-alpha,5-alpha-tetrahydrodeoxycorticosterone (THDOC) increased the durations of eIPSCs and sIPSCs in both δ−/−and δ+/+VB neurons. Our findings show that although the δ subunit confers a striking PS insensitivity to eIPSCs in VB neurons, it plays only a minor role in the synaptic inhibition of VB neurons. This suggests δ subunit containing GABAAreceptors may be functionally limited to an extrasynaptic locus in VB neurons.