Characterization of the Functional Cross-Talk between Surface GABA(A) and Dopamine D5 Receptors

The γ-aminobutyric acid type A receptor (GABA(A)R) plays a major role in fast inhibitory synaptic transmission and is highly regulated by the neuromodulator dopamine. In this aspect, most of the attention has been focused on the classical intracellular signaling cascades following dopamine G-protein-coupled receptor activation. Interestingly, the GABA(A)R and dopamine D5 receptor (D5R) have been shown to physically interact in the hippocampus, but whether a functional cross-talk occurs is still debated. In the present study, we use a combination of imaging and single nanoparticle tracking in live hippocampal neurons to provide evidence that GABA(A)Rs and D5Rs form dynamic surface clusters. Disrupting the GABA(A)R–D5R interaction with a competing peptide leads to an increase in the diffusion coefficient and the explored area of both receptors, and a drop in immobile synaptic GABA(A)Rs. By means of patch-clamp recordings, we show that this fast lateral redistribution of surface GABA(A)Rs correlates with a robust depression in the evoked GABAergic currents. Strikingly, it also shifts in time the expression of long-term potentiation at glutamatergic synapses. Together, our data both set the plasma membrane as the primary stage of a functional interplay between GABA(A)R and D5R, and uncover a non-canonical role in regulating synaptic transmission.