The cellular mechanisms underlying burst firing in substantia nigra dopamine neurons

Burst firing of substantia nigra dopamine (SN DA) neurons is an important teaching signal that instructs synaptic plasticity and associative learning. However, the synaptic and ionic mechanisms underlying this mode of activity are poorly understood. Previous research suggested that activation of NMDA receptors and/or G protein coupled receptor (GPCR)-mediated reduction of action potential (AP) afterhyperpolarization underlies burst activity. Moreover, theoretical studies proposed that activation of distal dendritic NMDA receptors amplifies oscillatory Ca2+ and Na+ channel currents to lead to the initiation of burst firing in SN DA neuron dendrites. To address the relative contribution of synaptic receptors and voltage-dependent ion channels, bursts were evoked using local electrical stimulation or pressure-pulse application of glutamate in brain slices, in the presence of GABA and D 2 dopamine receptor antagonists. The frequency, pattern and morphology of AP evoked under these conditions were similar to those observed in vivo.;My investigation revealed that burst firing and reductions in AP afterhyperpolarization were attenuated by application of AMPA or NMDA receptor selective antagonists and abolished by co-application of AMPA and NMDA antagonists. In contrast, application of glutamatergic and cholinergic GPCR antagonists moderately enhanced evoked activity. Dendritic pressure-pulse application of glutamate evoked burst firing that was similarly sensitive to antagonism of AMPA or NMDA receptors. Furthermore, the axon of SN DA neurons was typically found to originate from a large diameter dendrite that was proximal to the soma. However, in contrast to the predictions of earlier models: (1) somatic current injection generated firing that was similar in frequency and form to that observed in vivo; (2) the efficacy of glutamatergic excitation was inversely related to the distance of excitation from the axon; (3) pharmacological blockade or genetic deletion of Ca2+ channels did not prevent burst firing, although the former moderately reduced its intensity; (4) AP bursts were invariably detected first at sites that were proximal to the axon; (5) pharmacological blockade of Na+ channels in the vicinity of the axon/soma but not dendritic excitation impaired burst firing. Together these data suggest that SN DA neurons integrate their synaptic input in a more classical manner than was previously hypothesized.