FIGURE 11.

Model of the effects of the α1(AD) subunit on surface GABA_AR expression and isoform composition. This figure depicts our model of how the α1(AD) subunit reduces wild type surface GABA_AR expression and alters their composition. GABA_ARs assemble in the ER (A–C) and traffic to the plasma membrane (d--F). At maturity, wild type neurons (wt, A and D) predominantly express α1β2γ2 receptors (red) but also express non-α1-containing GABA_AR (depicted here as α3 GABA_AR, green), and thus we depicted a 6:2 ratio of α1β2γ2 to α3β2γ2 receptors. In a purely haploinsufficient model (B and E), all the misfolded α1(AD) subunit (blue) is degraded without it interacting with wild type GABA_AR. Therefore, haploinsufficient neurons express reduced α1β2γ2 receptors and unchanged non-α1-containing GABA_AR. The time course of the IPSC current kinetics would result from the currents contributed from α1 and α3 subunit containing receptors weighted by their abundance on the neuron surface. Therefore, as depicted here, the α1/α3 weighting would decrease from 6/2 in wild type neurons to 3/2 in α1 haploinsufficient neurons thus producing IPSCs that more resembled α3 subunit containing GABA_AR in the haploinsufficient neurons compared with wild type neurons. Our data are more consistent with a haploinsufficient plus dominant negative model (C and F). In this model, neurons degrade some α1(AD) subunit but also retain some misfolded α1(AD) subunit (blue) in the ER, which can associate with and retain a greater fraction of α3β2γ2 than α1β2γ2 receptors. This is shown here as α1(AD) retaining ⅓ α1 subunit containing receptors and ½ α3 subunit containing receptors. The retention of wild type GABA_AR expression in the haploinsufficient plus dominant negative case reduces IPSC peak amplitudes to a greater extent than in the α1 haploinsufficient neurons. In addition, the selective retention of α3 subunit containing receptors increases the α1/α3 weighting from 3/2 to 2/1 thus producing IPSC current kinetics that are more similar to α1 subunit containing GABA_AR than in the α1 haploinsufficient condition.