Intact synaptic GABAergic inhibition and altered neurosteroid modulation of thalamic relay neurons in mice lacking delta subunit.
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 gamma-aminobutyric acid-A (GABA(A)) receptors. Recombinant GABA(A) receptors containing the delta 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 GABA(A)-mediated synaptic inhibition in TC neurons would be affected by loss of the delta subunit. Spontaneous and evoked IPSCs were recorded from neurons in the ventral basal complex (VB) of the thalamus from brain slices of wild-type (delta(+/+)) and homozygous delta subunit deficient mice (delta(-/-)). Spontaneous IPSCs (sIPSCs) from delta(-/-) mice had no significant differences in amplitude, duration, or frequency compared with their delta(+/+) 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 delta(-/-) VB recordings. Evoked IPSCs (eIPSCs) in delta(-/-) 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 GABA(A) receptors was dependent on the presence of the delta subunit, as previously reported in recombinant systems. Pregnenolone sulfate (PS) significantly reduced eIPSC peak amplitude (-30%) and increased duration in delta(-/-), but not in delta(+/+) mice. sIPSCs were not affected in any neurons, delta(-/-) or delta(+/+). In contrast, 3-alpha,5-alpha-tetrahydrodeoxycorticosterone (THDOC) increased the durations of eIPSCs and sIPSCs in both delta(-/-) and delta(+/+) VB neurons. Our findings show that although the delta 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 delta subunit containing GABA(A) receptors may be functionally limited to an extrasynaptic locus in VB neurons.
Porcello
Darrell M
DM
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
Huntsman
Molly M
MM
Mihalek
Robert M
RM
Homanics
Gregg E
GE
Huguenard
John R
JR
D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D003900:Desoxycorticosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D009434:Neural Pathways; D011284:Pregnenolone / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D013788:Thalamus / Q000166:cytology / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000777:Anesthetics; D011963:Receptors, GABA-A; C018370:pregnenolone sulfate; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D005680:gamma-Aminobutyric Acid; D011284:Pregnenolone