Figure 4.

α4βδ GABA_ARs mediate a tonic current in NAc MSNs. A, Representative traces of whole-cell voltage-clamp recordings made from core MSNs derived from a WT and an α4^−/− mouse. The GABA_AR antagonist bicuculline (BIC 30 μm) produced an outward current and an associated decrease in membrane noise for the WT MSN, an effect greatly reduced for the equivalent recording from an α4^−/− MSN. The broken lines indicate the mean holding currents. The corresponding all-points histograms are given to the right of each trace (white = control, gray = + bicuculline). B, Illustrated are traces from representative MSNs giving the averaged superimposed mIPSCs recorded from neurons obtained from WT (black trace), α4^−/− (gray), and δ^−/− (light gray) mice, revealing that deletion of either of these subunits has no impact on the kinetics of the phasic currents mediated by synaptic receptors (note the amplitude is normalized to that of WT to aid a comparison of mIPSC time course). C, Representative traces illustrating that the selective δ-GABA_AR agonist THIP (1 μm) induces an inward current on a WT MSN, but has little effect on an equivalent neuron derived from an α4^−/− mouse. Note for the WT neuron that bicuculline (30 μm) reverses the THIP-induced inward current, but additionally induces an outward current (relative to the holding current before THIP), revealing again the presence of a tonic conductance cf. α4^−/− neurons. The broken lines indicate the mean holding current. The corresponding all-points histograms are given to the right of each trace [white = control; black = + THIP (1 μm); gray = THIP (1 μm) + bicuculline (30 μm)]. D, Histogram demonstrating that the mean outward current produced by bicuculline (30 μm; white columns) for WT neurons (n = 32) is greatly reduced for both α4^−/− (n = 12) and δ^−/− (n = 9) mice. Note that both D1- and D2-MSNs exhibit a tonic conductance as revealed by bicuculline (30 μm; white columns). Furthermore, the inward current produced by THIP (1 μm; gray columns) in WT neurons (n = 8), is greatly reduced for both α4^−/− (n = 9) and δ^−/− (n = 6) neurons. Similarly, DS2 (10 μm; black bars) produced an inward current in WT MSNs (n = 9), but was ineffective in equivalent recordings from α4^−/− (n = 7) or δ^−/− (n = 6) mice. The columns represent the mean ± SEM. **p < 0.01; ***p < 0.001, Student's unpaired t tests. E, The scatter plot reveals that all MSNs obtained from WT mice exhibit a large inward current response to either THIP (1 μm) or to DS2 (10 μm) that was greatly reduced or absent in equivalent MSNs from α4^−/− or δ^−/− MSNs. The horizontal bar represents the mean. Collectively, these data suggest that all NAc core MSNs express functional α4βδ GABA_ARs.