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

Abstract

. Dopaminergic neurons are subject to a significant background GABAergic input in vivo. The presence of this GABAergic background might be expected to inhibit dopaminergic neuron firing. However, dopaminergic neurons are not all silent but instead fire in single-spiking and burst firing modes. Here we present evidence that phasic changes in the tonic activity of GABAergic afferents are a potential extrinsic mechanism that triggers bursts and pauses in dopaminergic neurons. We find that spontaneous singlespiking is more sensitive to activation of GABA receptors than phasic N-methyl-D-aspartate (NMDA)-mediated burst firing in rat slices (P15-P31). Because tonic activation of GABA A receptors has previously been shown to suppress burst firing in vivo, our results suggest that the activity patterns seen in vivo are the result of a balance between excitatory and inhibitory conductances that interact with the intrinsic pacemaking currents observed in slices. Using the dynamic clamp technique, we applied balanced, constant NMDA and GABA A receptor conductances into dopaminergic neurons in slices. Bursts could be produced by disinhibition (phasic removal of the GABA A receptor conductance), and these bursts had a higher frequency than bursts produced by the same NMDA receptor conductance alone. Phasic increases in the GABA A receptor conductance evoked pauses in firing. In contrast to NMDA receptor, application of constant AMPA and GABA A receptor conductances caused the cell to go into depolarization block. These results support a bidirectional mechanism by which GABAergic inputs, in balance with NMDA receptormediated excitatory inputs, control the firing pattern of dopaminergic neurons.

Hub and switches: endocannabinoid signalling in midbrain dopamine neurons

“…Given that DA neurons are subject to major background GABA inputs [46] and that GABA afferents onto DA neurons arise from three diverse districts (i.e. ventral pallidum, RMTg nucleus, VTA), resulting in either inhibition of DA neuron spontaneous firing and/or triggering bursts and pauses in DA cells [17,47], it is crucial to dissect whether the diverse sets of synapses are equipped with discrete molecular architectures of a given endocannabinoid.…”

Dopamine neurons change the type of excitability in response to stimuli

“…Removal of inhibition in such conditions evokes a classical disinhibition burst (the disinhibition model of burst generation is well known and described in e.g. [35,[47][48][49] [35]. In this example, the simulated DA neuron is tonically active at 1.5 Hz during tonic co-activation of NMDA and GABA receptors (g NMDA = 16.9 m S/cm 2 , g GABA = 5mS/cm 2 ).…”

“…Balance of tonic NMDA and GABA inputs Our next goal was to reproduce the experimentally-observed compensatory influence of tonic NMDAR and GABAR conductances [35]. Using the dynamic clamp technique, it was shown in vitro that a balanced injection of GABAR and NMDAR conductances leads to DA neurons firing at frequencies comparable with background frequencies (1)(2)(3)(4)(5).…”

“…DA neurons are often identified by a prominent hyperpolarization-activated cation current (Ih), which gives a voltage "sag" upon injection of a hyperpolarizing current. It has been shown that Ih-expressing DA neurons exhibit smooth frequency decrease, pointing to a type I excitability [35,36]. However, the excitability type has been shown to vary depending on the intrinsic currents and network connectivity [42,43].…”

“…Further, injection of a tonic hyperpolarizing current to the regularly firing DA neuron in vitro increases its interspike intervals [7]. The firing properties of the neuron in response to a combination of tonic inhibitory and excitatory synaptic conductances were investigated by Lobb and colleagues [35,36]. Using the dynamic clamp technique, they injected inhibitory γ-Aminobutyric acid (GABA) and excitatory Nmethyl-D-aspartate (NMDA) receptor conductances in SNc DA neurons.…”