Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact

Abstract

Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal pathology in MS remain elusive. Evidence suggests that axonal pathology is a direct consequence of demyelination, as we and others have shown that the node of Ranvier disassembles following loss of myelin. In contrast to the node of Ranvier, we now show that the axon initial segment (AIS), the axonal domain responsible for action potential initiation, remains intact following cuprizone-induced cortical demyelination. Instead, we find that the AIS is disrupted in the neocortex of mice that develop experimental autoimmune encephalomyelitis (EAE) independent of local demyelination. EAE-induced mice demonstrate profound compromise of AIS integrity with a progressive disruption that corresponds to EAE clinical disease severity and duration, in addition to cortical microglial reactivity. Furthermore, treatment with the drug didox results in attenuation of AIS pathology concomitantly with microglial reversion to a less reactive state. Together, our findings suggest that inflammation, but not demyelination, disrupts AIS integrity and that therapeutic intervention may protect and reverse this pathology. GLIA 2016;64:1190-1209.

Mild Traumatic Brain Injury Evokes Pyramidal Neuron Axon Initial Segment Plasticity and Diffuse Presynaptic Inhibitory Terminal Loss

“…Consistent with previous reports from our laboratory and others (Greer et al, 2013; Gutzmann et al, 2014; Clark et al, 2016), ankG labeling throughout the neocortex was restricted to the AIS and nodes of Ranvier (Figure 3B). Importantly, ankG labeling of intact YFP+ pyramidal neurons clearly delineated the AIS in sections from both sham and mTBI mice (Figures 6B,E).…”

Axonal Membranes and Their Domains: Assembly and Function of the Axon Initial Segment and Node of Ranvier

“…However, they observed no changes in ankyrin-G, βIV-spectrin and Nav1.6 expression at the AIS following demyelination (Hamada and Kole, 2015). Consistent with these findings, Clark et al (2016) also found AIS components remained intact following cuprizone-induced demyelination. In contrast, the authors discovered the proper clustering of ankyrin-G, βIV-spectrin and Nav1.6 was lost at the AIS of mice after chronic exposure of experimental autoimmune encephalomyelitis (EAE), an inflammatory model of MS (Clark et al, 2016).…”

“…Consistent with these findings, Clark et al (2016) also found AIS components remained intact following cuprizone-induced demyelination. In contrast, the authors discovered the proper clustering of ankyrin-G, βIV-spectrin and Nav1.6 was lost at the AIS of mice after chronic exposure of experimental autoimmune encephalomyelitis (EAE), an inflammatory model of MS (Clark et al, 2016). Ultimately, the AIS is a primary target during inflammation and, in addition to demyelination of the distal axon, may contribute to inflammatory demyelinating diseases such as MS.…”

The Segregated Expression of Voltage-Gated Potassium and Sodium Channels in Neuronal Membranes: Functional Implications and Regulatory Mechanisms

“…Multiple pathological mechanisms can lead to impairment of normal AIS and nodes organization and the functional distribution of Nav and Kv channels along the axon (Buffington and Rasband, 2011; Normand and Rasband, 2015; Clark et al, 2016; Griggs et al, 2017). Mutations affecting the cytoskeletal organization typical of these structures, notably AnkG are implicated in a broad range of cognitive disorders (Normand and Rasband, 2015).…”