Cellular Mechanisms Underlying Burst Firing in Substantia Nigra Dopamine Neurons

Abstract

Burst firing of substantia nigra dopamine (SN DA) neurons is believed to represent an important teaching signal that instructs synaptic plasticity and associative learning. However, the mechanisms through which synaptic excitation overcomes the limiting effects of somatic Ca 2ϩ -dependent K ϩ current to generate burst firing are controversial. Modeling studies suggest that synaptic excitation sufficiently amplifies oscillatory dendritic Ca 2ϩ and Na ϩ channel currents to lead to the initiation of high-frequency firing in SN DA neuron dendrites. To test this model, visually guided compartment-specific patch-clamp recording and ion channel manipulation were applied to rodent SN DA neurons in vitro.As suggested previously, 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 the model, (1) somatic current injection generated firing that was similar in frequency and form to burst firing 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 Ca 2ϩ channels did not prevent high-frequency firing, (4) action potential bursts were invariably detected first at sites that were proximal to the axon, and (5) pharmacological blockade of Na ϩ 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 conventional manner than was hypothesized previously.

Mechanisms for multiple activity modes of VTA dopamine neurons

“…These findings are in line with experimental findings and complement previous theoretical modeling efforts, however in a single compartment framework as somatodendritic interactions appear to not be a necessary for burst firing initiation [13,14] (in particular the distal . CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

“…Existing models can capture a variety of these behaviors [10][11][12], yet are not without their shortcomings. The models of [10][11][12] rely on somatodendritic interactions as underlying burst generation, however, two laboratories have experimental findings that suggest burst firing is somatically induced [13,14]. These somatically induced bursts have characteristics consistent with normal bursting, suggesting that a single-compartmental model should be sufficient for generating the observed DA neuronal dynamics.…”

A reduced model of DA neuronal dynamics that displays quiescence, tonic firing and bursting

“…Other models depend on the interaction between the activity at the soma and the dendrites [10,11,9] in order to produce bursting dynamics (with this approach certain parameters may be unobservable). However, recent experimental findings [12,13] indicate that burst firing can be generated somatically with the dendrites silenced. These somatically induced bursts had characteristics consistent with normal bursting, suggesting that a single-compartmental model should be sufficient for generating the observed DA neuronal dynamics.…”

Dopamine neurons change the type of excitability in response to stimuli

“…In these models, a high maximal frequency (>10 Hz) can be achieved by tonic activation of the AMPAR or in response to depolarizing current injection, which contradicts experimental observations [7,34]. To the contrary, a number of experimental studies suggest that stimulation of NMDA receptors evokes a burst of high-frequency firing, whereas AMPA receptor activation evokes modest increases in firing [37][38][39][40] (but see [61,71]). This is an important distinction, which impacts the excitability of the neuron.…”

“…The DA population is electrophysiologically heterogeneous [60][61][62], and its uncoordinated activity produces a homogeneous low-level DA concentration. In order to have similar firing rates and basal DA levels in both cases, we balanced the increase in firing rate produced by the application of AMPAR conductance with GABAR conductance (note that GABA can balance AMPA only for a very limited range of values).…”