Impact of Unitary Synaptic Inhibition on Spike Timing in Ventral Tegmental Area Dopamine Neurons

Abstract

Midbrain dopamine neurons receive convergent synaptic input from multiple brain areas, which perturbs rhythmic pacemaking to produce the complex firing patterns observed in vivo. This study investigated the impact of single and multiple inhibitory inputs on ventral tegmental area (VTA) dopamine neuron firing in mice of both sexes using novel experimental measurements and modeling. We first measured unitary inhibitory postsynaptic currents (uIPSCs) produced by single axons using both minimal electrical stimulation and minimal optical stimulation of rostromedial tegmental nucleus (RMTg) and ventral pallidum (VP) afferents. We next determined the phase resetting curve (PRC), the reversal potential for GABAAreceptor-mediated IPSCs, and the average inter-spike membrane potential trajectory during pacemaking. We combined these data in a phase oscillator model of a VTA dopamine neuron, simulating the effects of unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and rate. The effect of a uIPSG on spike timing was predicted to vary according to its timing within the inter-spike interval (ISI), or phase. Simulations were performed to predict the pause duration resulting from synchronous arrival of multiple uIPSGs, and the changes in firing rate and regularity produced by asynchronous uIPSGs. The model data suggest that asynchronous inhibition is more effective than synchronous inhibition, because it tends to hold the neuron at membrane potentials well positive to the IPSC reversal potential. Our results indicate that small fluctuations in the inhibitory synaptic input arriving from the many afferents to each dopamine neuron are sufficient to produce highly variable firing patterns like those observed in vivo.Significance StatementThis study dissects the input-output relationship of VTA dopamine neurons receiving inputs from single presynaptic inhibitory neurons. We measured unitary IPSCs from two major inhibitory inputs (the RMTg and VP) and simulated their impact on dopamine neuron firing based on new experimental data including the phase resetting curve (PRC) and the reversal potential of the GABAAreceptor-mediated currents. The results predict the impact of single and multiple unitary inhibitory postsynaptic conductances (uIPSGs) on spike timing and suggest that asynchronous, low-frequency inhibition can summate in a supralinear manner to powerfully slow or halt a dopamine neuron's firing.