Covariation of axon initial segment location and dendritic tree normalizes the somatic action potential

Abstract

In mammalian neurons, the axon initial segment (AIS) electrically connects the somatodendritic compartment with the axon and converts the incoming synaptic voltage changes into a temporally precise action potential (AP) output code. Although axons often emanate directly from the soma, they may also originate more distally from a dendrite, the implications of which are not wellunderstood. Here, we show that one-third of the thick-tufted layer 5 pyramidal neurons have an axon originating from a dendrite and are characterized by a reduced dendritic complexity and thinner main apical dendrite. Unexpectedly, the rising phase of somatic APs is electrically indistinguishable between neurons with a somatic or a dendritic axon origin. Cable analysis of the neurons indicated that the axonal axial current is inversely proportional to the AIS distance, denoting the path length between the soma and the start of the AIS, and to produce invariant somatic APs, it must scale with the local somatodendritic capacitance. In agreement, AIS distance inversely correlates with the apical dendrite diameter, and model simulations confirmed that the covariation suffices to normalize the somatic AP waveform. Therefore, in pyramidal neurons, the AIS location is finely tuned with the somatodendritic capacitive load, serving as a homeostatic regulation of the somatic AP in the face of diverse neuronal morphologies.T he axon initial segment (AIS) specifies in vertebrate neurons a single domain for the final integration of synaptic input and the initiation of action potentials (APs) (1, 2). To rapidly produce large inward and outward currents mediating the AP, the AIS contains a complex arrangement of cytoskeletal and transmembrane proteins clustering high densities of voltage-gated sodium (Nav) and potassium (Kv) channels in the axolemma (2-4). Although the composition of ion channels is critical for initiation and regulation of firing patterns, there are emerging insights that the AIS is not operating in isolation but is also subject to activity-dependent changes in size and location constrained by the local dendritic branch geometry and the passive cable properties (5-7). Experimental studies linking changes in AIS length and neuronal output showed that an increased length facilitates AP generation (6,8). In these cases, the net increased excitability is a logical consequence of the larger Nav conductance. However, predicting the impact of AIS location on neuronal output is more complex. Experimental studies showed that an activity-dependent distal shift of the AIS is associated with decreased AP output (5). In contrast, model simulations showed that shifting the AIS distally promotes excitability (9). One of the critical factors influencing AIS excitability is the large somatodendritic membrane area acting as current sink for sodium current generated in the AIS (10-12). In this view, a distal anatomical location of the AIS increases electrical compartmentalization and facilitates axonal AP generation. Indeed, the local depolarization in the...

Characterization of the axon initial segment of mice substantia nigra dopaminergic neurons

“…Given the lack of a strong synaptic innervation at the AIS itself, synaptic regulation of dopaminergic neurons may be facilitated by innervation of regions near the AIS, specifically those of the axon bearing dendrite, which in both dopaminergic and hippocampal neurons (Blythe et al, 2009;Hamada, Goethals, de Vries, Brette, & Kole, 2016) has been shown to be particularly important for action potential generation and neuronal excitability.…”

Theoretical relation between axon initial segment geometry and excitability

“…In some studies, distal displacement of the AIS is associated with decreased excitability (Grubb 33 and Burrone, 2010; Hatch et al, 2017; Lezmy et al, 2017;Wefelmeyer et al, 2015). In others, neurons 34 with more distal AIS have an identical (Thome et al, 2014) or slightly hyperpolarized threshold 35 (Hamada et al, 2016). Thus, it is challenging to experimentally isolate the specific contribution of AIS 36 geometry to excitability changes.…”

Cannabinoid Receptors Modulate Neuronal Morphology and AnkyrinG Density at the Axon Initial Segment

“…Also, a recent study from the Südhof laboratory described a tight relationship between dendritic size, axonal growth and ankyrinG density at the AIS in neurons after L1CAM conditional deletion (Patzke et al, 2016). Moreover, a very recent study demonstrates that AIS distance to the soma in cortical layer 5 pyramidal adult neurons inversely correlates with dendritic complexity (Hamada et al, 2016), supporting the idea that dendritic morphology and AIS might be regulated in a coordinated manner in several neuronal types. Taking these studies and our results into account, change in dendritic morphology induced by CB1R lack of function is the more plausible hypothesis to explain AIS changes.…”