Inactivation mode of sodium channels defines the different maximal firing rates of conventional versus atypical midbrain dopamine neurons

Abstract

Two subpopulations of midbrain dopamine (DA) neurons are known to have different dynamic firing ranges in vitro that correspond to distinct projection targets: the originally identified conventional DA neurons project to the dorsal striatum and the lateral shell of the nucleus accumbens, whereas an atypical DA population with higher maximum firing frequencies projects to prefrontal regions and other limbic regions including the medial shell of nucleus accumbens. Using a computational model, we show that previously identified differences in biophysical properties do not fully account for the larger dynamic range of the atypical population and predict that the major difference is that originally identified conventional cells have larger occupancy of voltage-gated sodium channels in a long-term inactivated state that recovers slowly; stronger sodium and potassium conductances during action potential firing are also predicted for the conventional compared to the atypical DA population. These differences in sodium channel gating imply that longer intervals between spikes are required in the conventional population for full recovery from long-term inactivation induced by the preceding spike, hence the lower maximum frequency. These same differences can also change the bifurcation structure to account for distinct modes of entry into depolarization block: abrupt versus gradual. The model predicted that in cells that have entered depolarization block, it is much more likely that an additional depolarization can evoke an action potential in conventional DA population. New experiments comparing lateral to medial shell projecting neurons confirmed this model prediction, with implications for differential synaptic integration in the two populations.

Long-Term Inactivation of Sodium Channels as a Mechanism of Adaptation in CA1 Pyramidal Neurons

“…Adaptation due to long-term inactivation of Na V channels has been observed in serotonergic raphe neurons (Navarro et al, 2020). Long-term inactivation of Na V channels has also recently been demonstrated to control not only adaptation, but also entry into depolarization block in different subpopulations of midbrain dopamine neurons (Knowlton et al, 2021). We conclude that long-term inactivation of Na V channels may be quite generally utilized as a mechanism for spike frequency adaptation in the central nervous system.…”

“…Much more complicated Markov models of Na V gating exist (Goldfarb, 2012;Navarro et al, 2020), but we attempted to use the simplest model possible to gain insight into long-term inactivation. We started with a published six-state model (Balbi et al, 2017) and removed one open state (Knowlton et al, 2021) and one closed state, leaving the four-state model as in Figure 1D1. Figure 10 recapitulates the main features of the model and how the various states/pools differentially regulate adaptation and spike height during the train.…”

“…The copyright holder for this preprint this version posted January 31, 2022. ; https://doi.org/10. 1101/2021 Adaptation can result from accumulation of an outward current or a decrement in an inward current active in the inter-spike interval. The Ca 2+ -activated small-conductance K + current (I SK ) (Stocker et al, 1999;Pedarzani et al, 2005) and the muscarinic M-type K + current (I M ) (Otto et al, 2006;Gu et al, 2008) are often implicated in firing rate adaptation in CA1 pyramidal neurons.…”

SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons

“…The depolarizing currents active between action potentials include persistent voltage-gated and leak sodium currents ( Grace and Onn, 1989 ; Grace, 1991 ; Puopolo et al, 2007 ; Khaliq and Bean, 2010 ; Philippart and Khaliq, 2018 ; Um et al, 2021 ), low-threshold calcium currents ( Grace and Onn, 1989 ; Grace, 1991 ; Yung et al, 1991 ; Kang and Kitai, 1993a , b ; Wilson and Callaway, 2000 ; Takada et al, 2001 ; Wolfart and Roeper, 2002 ; Chan et al, 2007 ; Puopolo et al, 2007 ; Philippart et al, 2016 ), and the hyperpolarization-activated cyclic nucleotide-dependent (HCN) current ( Neuhoff et al, 2002 ). If unopposed, these currents would produce fast burst firing, rapidly leading to sodium channel inactivation and depolarization block ( Knowlton et al, 2021 ).…”

Protracted morphine withdrawal corresponds with sex-specific alterations to motivated behavior and mesoaccumbal subcircuit dopamine cell plasticity

“…One possible explanation for the increased rheobase is an adapted function and/ or expression of factors supporting intrinsic excitability. DA cell firing properties and responsivity have been shown to rely on several ion channel functions and other postsynaptic mechanisms sensitive to drugs, including opioids [90][91][92][93][94][95] . Potassium current alterations may be the most parsimonious candidate, being an opioid-sensitive direct modulator of intrinsic excitability 96 .…”