Abstract
Substantia nigra pars compacta (SNc) dopaminergic (DA) neurons display a peculiar electrical phenotype characterized in vitro by a spontaneous tonic regular activity (pacemaking activity), a broad action potential and a biphasic post-inhibitory response. The transient A-type current (IA) is known to play a crucial role in this electrical phenotype, and so far this current was considered to be carried exclusively by Kv4.3 potassium channels. Using Kv4.3-/- transgenic mice, we demonstrate that the constitutive loss of this channel is associated with increased exploratory behavior and impaired motor learning at the behavioral level. Consistently it is also associated with a lack of compensatory changes in other ion currents at the cellular level. Using antigen retrieval immunohistochemistry, we then demonstrate that Kv4.2 potassium channels are also expressed in SNc DA neurons, even though their contribution to IA appears significant only in a minority of neurons (∼5-10%). Using correlative analysis on recorded electrophysiological parameters and multi-compartment modeling, we then demonstrate that, rather than its conductance level, IA gating kinetics (inactivation time constant) appear as the main biophysical property defining post-inhibitory rebound delay and pacemaking frequency. Moreover, we show that the hyperpolarization-activated current (IH) has an opposing and complementary influence on the same firing features.
SIGNIFICANCE STATEMENT
Substantia nigra pars compacta (SNc) dopaminergic (DA) neurons are characterized by pacemaking activity, a broad action potential and biphasic post-inhibitory response. The A-type transient potassium current (IA) plays a central role in this electrical phenotype. While it was thought so far that Kv4.3 ion channels were fully responsible for IA, using a Kv4.3-/- transgenic mouse and antigen retrieval immunohistochemistry we demonstrate that Kv4.2 channels are also expressed in SNc DA neurons, although their contribution is significant in a minority of neurons only. Using electrophysiological recordings and computational modeling, we then demonstrate that IA gating kinetics and its functional complementarity with the hyperpolarization-activated current are major determinants of both pacemaking activity and post-inhibitory response in SNc DA neurons.
Footnotes
the authors declare no competing financial interests.
This work was supported by the European Research Council (Consolidator grant 616827 CanaloHmics to J-M.G., supporting A.H-H. and M.T.), the Fondation de France (grant 00076344 to J-M.G. and M.A., supporting A.H-H.), and the Agence Nationale pour la Recherche (ANR Logik ANR-17-CE16-0022, supporting J.R.F.). We thank O. Toutendji for technical assistance.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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