Abstract
SummaryNeurons implement a variety of plasticity mechanisms to alter their function over timescales ranging from seconds to days. One powerful means of controlling excitability is to directly modulate the site of spike initiation, the axon initial segment (AIS). However, all plastic structural AIS changes reported thus far have been slow, involving days of neuronal activity perturbation. Here, we show that AIS plasticity can be induced much more rapidly. Just 3 hr of elevated activity significantly shortened the AIS of dentate granule cells in a calcineurin-dependent manner. The functional effects of rapid AIS shortening were offset by dephosphorylation of voltage-gated sodium channels, another calcineurin-dependent mechanism. However, pharmacological separation of these phenomena revealed a significant relationship between AIS length and repetitive firing. The AIS can therefore undergo a rapid form of structural change over timescales that enable interactions with other forms of activity-dependent plasticity in the dynamic control of neuronal excitability.
Highlights
The axon initial segment (AIS) is a molecularly defined specialization of the proximal axon that, because of its morphology, cable properties, and high density of voltage-gated sodium channels, is the site for action potential (AP) initiation (Bender and Trussell, 2012; Clark et al, 2009; Kole and Stuart, 2012)
Immunofluorescent labeling for the scaffolding molecule ankyrin-G (AnkG) was used to quantify AIS length in dentate granule cells (DGCs) identified by prox1 expression (Evans et al, 2013; Williams et al, 2011)
We observed rapid shortening of the AIS in ChR2+ DGCs exposed to more naturalistic photostimuli, drawing inter-flash intervals from a distribution where two orthogonal parameters— frequency and ‘burstiness’’—uniquely define the pattern of stimulus timing (Shimokawa et al, 2010)
Summary
The axon initial segment (AIS) is a molecularly defined specialization of the proximal axon that, because of its morphology, cable properties, and high density of voltage-gated sodium channels, is the site for action potential (AP) initiation (Bender and Trussell, 2012; Clark et al, 2009; Kole and Stuart, 2012) With such a crucial role in the determination of neuronal excitability, it is perhaps no surprise that the AIS is a target for considerable modulation and plasticity (Grubb et al, 2011). In vivo, removing presynaptic input to auditory nucleus magnocellularis neurons can result in a significantly lengthened AIS after 3 days (Kuba et al, 2010) This structural plasticity at the AIS is associated with alterations in excitability (Grubb and Burrone, 2010; Kuba et al, 2010; Wefelmeyer et al, 2015) and may contribute to long-term control of AP firing. Is it possible for AIS structure to change this quickly?
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