Robustness to Axon Initial Segment Variation Is Explained by Somatodendritic Excitability in Rat Substantia Nigra Dopaminergic Neurons

Abstract

In many neuronal types, axon initial segment (AIS) geometry critically influences neuronal excitability. Interestingly, the axon of rat SNc dopaminergic (DA) neurons displays a highly variable location and most often arises from an axon-bearing dendrite (ABD). We combined current-clamp somatic and dendritic recordings, outside-out recordings of dendritic sodium and potassium currents, morphological reconstructions and multicompartment modeling on male and female rat SNc DA neurons to determine cell-to-cell variations in AIS and ABD geometry, and their influence on neuronal output (spontaneous pacemaking frequency, action potential [AP] shape). Both AIS and ABD geometries were found to be highly variable from neuron to neuron. Surprisingly, we found that AP shape and pacemaking frequency were independent of AIS geometry. Modeling realistic morphological and biophysical variations helped us clarify this result: in SNc DA neurons, the complexity of the ABD combined with its excitability predominantly define pacemaking frequency and AP shape, such that large variations in AIS geometry negligibly affect neuronal output and are tolerated. In many neuronal types, axon initial segment (AIS) geometry critically influences neuronal excitability. In the current study, we describe large cell-to-cell variations in AIS length or distance from the soma in rat substantia nigra pars compacta dopaminergic neurons. Using neuronal reconstruction and electrophysiological recordings, we show that this morphological variability does not seem to affect their electrophysiological output, as neither action potential properties nor pacemaking frequency is correlated with AIS morphology. Realistic multicompartment modeling suggests that this robustness to AIS variation is mainly explained by the complexity and excitability of the somatodendritic compartment.

Diversity of Axonal and Dendritic Contributions to Neuronal Output

“…Since the seminal observation of Hausser et al (1995), faithful back-propagation has been described in at least two other mammalian cell types, the olfactory bulb mitral cells (Figure 2A; Bischofberger and Jonas, 1997;Chen et al, 1997;Xiong and Chen, 2002) and the oriens-alveus interneurons of the hippocampus ( Figure 2B; Martina et al, 2000). Interestingly, these three cell types share a common property, in that they express a rather high density of sodium channels at the dendritic level: the measured conductance density is ∼75, ∼80 and ∼110 pS/µm 2 in dopaminergic neurons (Moubarak et al, 2019), mitral cells (Bischofberger and Jonas, 1997) and oriens-alveus interneurons (Martina et al, 2000), respectively. Moreover, these three cell types present morphological peculiarities favoring AP back-propagation.…”

“…This cell type has the particularity of spontaneously generating at a regular frequency (pacemaking activity) broad biphasic APs, suggesting a strong involvement of SD sodium channels (Grace and Bunney, 1983). Two interesting observations were made in this cell type: (i) the axon mainly arises from a dendrite (axon-bearing dendrite or ABD), at distances from the soma reaching 200 µm (Figure 2A; Hausser et al, 1995;Gentet and Williams, 2007;Meza et al, 2018;Moubarak et al, 2019); and (ii) the AP recorded in different compartments of the neuron (ABD, soma or non-ABD) shows virtually no attenuation in its amplitude ( Figure 2B) although it is always initiated at the AIS (Hausser et al, 1995;Gentet and Williams, 2007;Moubarak et al, 2019). This faithful back-propagation, which appears highly reliable during spontaneous pacemaking (Gentet and Williams, 2007;Blythe et al, 2009;Moubarak et al, 2019) may be abolished under specific conditions, for instance when barrages of EPSPs onto the ABD are used to trigger firing or when dopamine is used to dampen somatic excitability (Gentet and Williams, 2007).…”

“…Two interesting observations were made in this cell type: (i) the axon mainly arises from a dendrite (axon-bearing dendrite or ABD), at distances from the soma reaching 200 µm (Figure 2A; Hausser et al, 1995;Gentet and Williams, 2007;Meza et al, 2018;Moubarak et al, 2019); and (ii) the AP recorded in different compartments of the neuron (ABD, soma or non-ABD) shows virtually no attenuation in its amplitude ( Figure 2B) although it is always initiated at the AIS (Hausser et al, 1995;Gentet and Williams, 2007;Moubarak et al, 2019). This faithful back-propagation, which appears highly reliable during spontaneous pacemaking (Gentet and Williams, 2007;Blythe et al, 2009;Moubarak et al, 2019) may be abolished under specific conditions, for instance when barrages of EPSPs onto the ABD are used to trigger firing or when dopamine is used to dampen somatic excitability (Gentet and Williams, 2007). Since the seminal observation of Hausser et al (1995), faithful back-propagation has been described in at least two other mammalian cell types, the olfactory bulb mitral cells (Figure 2A; Bischofberger and Jonas, 1997;Chen et al, 1997;Xiong and Chen, 2002) and the oriens-alveus interneurons of the hippocampus ( Figure 2B; Martina et al, 2000).…”

Brief sensory deprivation triggers cell type-specific structural and functional plasticity in olfactory bulb neurons

“…While this peculiar axonal arrangement challenges the traditional view on neuronal input-output transformation (Kaifosh and Losonczy, 2014), it is not unique to bulbar DA neurons. Indeed, midbrain DA neurons have been shown to carry "dendrite-origin" AISes (González-Cabrera et al, 2017;Yang et al, 2019), and recently the overall variability in AIS length and location in these neurons has been proposed to play a key role in the maintenance of an appropriate pacemaking rhythm in the context of variable dendritic branching (Moubarak et al, 2019). Moreover, "dendriteorigin" AISes are not exclusive to DA neurons: common in invertebrates (Triarhou, 2014), they have also been described in cat and mouse cortex (Hamada et al, 2016;Höfflin et al, 2017;Meyer and Wahle, 1988), in hippocampal pyramidal cells (Thome et al, 2014), and in cerebellar granule cells (Houston et al, 2017).…”

Author response: Theoretical relation between axon initial segment geometry and excitability

“…The theory also assumes that the AIS is electrically close to the soma (i.e., relative to the axonal space length). In some neurons, such as dopaminergic neurons (González-Cabrera et al, 2017;Meza et al, 2018;Moubarak et al, 2019), this assumption may not hold and specific theoretical developments might be necessary.…”