| First Author | Suryanarayanan A | Year | 2011 |
| Journal | Front Neurosci | Volume | 5 |
| Pages | 110 | PubMed ID | 21977012 |
| Mgi Jnum | J:190198 | Mgi Id | MGI:5448366 |
| Doi | 10.3389/fnins.2011.00110 | Citation | Suryanarayanan A, et al. (2011) Subunit Compensation and Plasticity of Synaptic GABA(A) Receptors Induced by Ethanol in alpha4 Subunit Knockout Mice. Front Neurosci 5:110 |
| abstractText | There is considerable evidence that ethanol (EtOH) potentiates gamma-aminobutyric acid type A receptor (GABA(A)R) action, but only GABA(A)Rs containing delta subunits appear sensitive to low millimolar EtOH. The alpha4 and delta subunits co-assemble into GABA(A)Rs which are relatively highly expressed at extrasynaptic locations in the dentate gyrus where they mediate tonic inhibition. We previously demonstrated reversible- and time-dependent changes in GABA(A)R function and subunit composition in rats after single-dose EtOH intoxication. We concluded that early tolerance to EtOH occurs by over-activation and subsequent internalization of EtOH-sensitive extrasynaptic alpha4betadelta-GABA(A)Rs. Based on this hypothesis, any highly EtOH-sensitive GABA(A)Rs should be subject to internalization following exposure to suitably high EtOH doses. To test this, we studied the GABA(A)Rs in mice with a global deletion of the alpha4 subunit (KO). The dentate granule cells of these mice exhibited greatly reduced tonic currents and greatly reduced potentiation by acutely applied EtOH, whereas synaptic currents showed heightened sensitivity to low EtOH concentrations. The hippocampus of naive KO mice showed reduced delta subunit protein levels, but increased alpha2, and gamma2 levels compared to wild-type (WT) controls, suggesting at least partial compensation by these subunits in synaptic, highly EtOH-sensitive GABA(A)Rs of KO mice. In WT mice, cross-linking and Western blot analysis at 1 h after an EtOH challenge (3.5 g/kg, i.p.) revealed increased intracellular fraction of the alpha1, alpha4, and delta, but not alpha2, alpha5, or gamma2 subunits. By contrast, we observed significant internalization of alpha1, alpha2, delta, and gamma2 subunits after a similar EtOH challenge in KO mice. Synaptic currents from naive KO mice were more sensitive to potentiation by zolpidem (0.3 muM, requiring alpha1/alpha2, inactive at alpha4/5 GABA(A)Rs) than those from naive WT mice. At 1 h after EtOH, synaptic currents of WT mice were unchanged, whereas those of KO mice were significantly less sensitive to zolpidem, suggesting decreases in functional alpha1/2betagamma GABA(A)Rs. These data further support our hypothesis that EtOH intoxication induces GABA(A)R plasticity via internalization of highly EtOH-sensitive GABA(A)Rs. |
