A Dynamic Role for GABA Receptors on the Firing Pattern of Midbrain

22 Dopaminergic neurons are subject to a significant background GABAergic input 23 in vivo. The presence of this GABAergic background might be expected to inhibit 24 dopaminergic neuron firing. However, dopaminergic neurons are not all silent but instead 25 fire in single-spiking and burst firing modes. Here we present evidence that phasic 26 changes in the tonic activity of GABAergic afferents are a potential extrinsic mechanism 27 that triggers bursts and pauses in dopaminergic neurons. We find that spontaneous single28 spiking is more sensitive to activation of GABA receptors than phasic NMDA-mediated 29 burst firing in rat slices (P15-P31). Since tonic activation of GABAA receptors has 30 previously been shown to suppress burst firing in vivo, our results suggest that the 31 activity patterns seen in vivo are the result of a balance between excitatory and inhibitory 32 conductances that interact with the intrinsic pacemaking currents observed in slices. 33 Using the dynamic clamp technique, we applied balanced, constant NMDA and GABAA 34 receptor conductances into dopaminergic neurons in slices. Bursts could be produced by 35 disinhibition (phasic removal of the GABAAR conductance) and these bursts had a higher 36 frequency than bursts produced by the same NMDAR conductance alone. Phasic 37 increases in the GABAAR conductance evoked pauses in firing. In contrast to NMDAR, 38 application of constant AMPAR and GABAAR conductances caused the cell to go into 39 depolarization block. These results support a bidirectional mechanism by which 40 GABAergic inputs, in balance with NMDAR-mediated excitatory inputs, control the 41 firing pattern of dopaminergic neurons. 42