Functional implications of axon initial segment cytoskeletal disruption in stroke

Abstract

Axon initial segment (AIS) is the proximal part of the axon, which is not covered with a myelin sheath and possesses a distinctive, specialized assembly of voltage-gated ion channels and associated proteins. AIS plays critical roles in synaptic integration and action potential generation in central neurons. Recent evidence shows that stroke causes rapid, irreversible calpain-mediated proteolysis of the AIS cytoskeleton of neurons surrounding the ischemic necrotic core. A better understanding of the molecular mechanisms underlying this "non-lethal" neuronal damage might provide new therapeutic strategies for improving stroke outcome. Here, we present a brief overview of the structure and function of the AIS. We then discuss possible mechanisms underlying stroke-induced AIS damage, including the roles of calpains and possible sources of Ca 2+ ions, which are necessary for the activation of calpains. Finally, we discuss the potential functional implications of the loss of the AIS cytoskeleton and ion channel clusters for neuronal excitability.

Oxidative Stress Induces Disruption of the Axon Initial Segment

“…Calcium (Ca 2+ ) is central to most previously identified mechanisms of AIS modulation, during both activity-dependent plasticity ( Yamada and Kuba, 2016 ) as well as pathological insult ( Stoler and Fleidervish, 2016 ). To determine if ROS/RNS-induced AIS disruption involves extracellular Ca 2+ entry, neurons were pretreated with the nonmembrane permeable Ca 2+ -chelating agent EGTA, prior to SIN-1 addition.…”

Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity

“…Although several reports on the development of enteropathy by single dose of diclofenac in animal model exist [37][38][39][40][41] , the dosages of diclofenac used in these studies were much higher than the clinical dosage. The present study showed that rats orally treated with 10 mg/kg of diclofenac (equivalent to a clinical dosage of 120 mg in a 70 kg human) daily for 6 d also developed typical enteropathy.…”

Dynamic Gain Analysis Reveals Encoding Deficiencies in Cortical Neurons That Recover from Hypoxia-Induced Spreading Depolarizations

“…Recently, this was also demonstrated experimentally (Ilin et al, 2013;Lazarov et al, 2018). APs originate in the axon initial segment (AIS), a highly specialized cytoskeletal structure organized around Ankyrin G (AnkG), which is the main scaffold protein responsible for anchoring the ion channels involved in AP initiation (Grubb and Burrone, 2010;Rasband, 2010;Stoler and Fleidervish, 2016). It was shown that, in a mouse model of stroke, arterial occlusion leads to a major disruption of AIS scaffold proteins, due to activation of the Ca 2ϩ -dependent protease, calpain (Schafer et al, 2009).…”