Oxidative Stress Induces Disruption of the Axon Initial Segment

Clark, Kareem C.; Sword, Brooke A.; Dupree, Jeffrey L.

doi:10.1177/1759091417745426

Cited by 24 publications

(21 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pathological AIS alterations are mediated by calpain, a calcium-dependent cysteine protease, in models of stroke (Schafer et al, 2009 ), induced excitotoxicity (Del Puerto et al, 2015 ; Benned-Jensen et al, 2016 ), and multiple sclerosis (Clark et al, 2016 ). In addition, hyperphosphorylated tau (Hatch et al, 2017 ) or oxidative stress followed by calpain activation (Clark et al, 2017 ) induce pathological alterations of AIS. Calcium/calmodulin-dependent kinase II (CaMKII) may regulate excitability through its interaction with ankyrinG and βIV spectrin complex that anchor it to the AIS (Hund et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Type 2 Diabetes Leads to Axon Initial Segment Shortening in db/db Mice

Yermakov

Drouet

Griggs

et al. 2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Cognitive and mood impairments are common central nervous system complications of type 2 diabetes, although the neuronal mechanism(s) remains elusive. Previous studies focused mainly on neuronal inputs such as altered synaptic plasticity. Axon initial segment (AIS) is a specialized functional domain within neurons that regulates neuronal outputs. Structural changes of AIS have been implicated as a key pathophysiological event in various psychiatric and neurological disorders. Here we evaluated the structural integrity of the AIS in brains of db/db mice, an established animal model of type 2 diabetes associated with cognitive and mood impairments. We assessed the AIS before (5 weeks of age) and after (10 weeks) the development of type 2 diabetes, and after daily exercise treatment of diabetic condition. We found that the development of type 2 diabetes is associated with significant AIS shortening in both medial prefrontal cortex and hippocampus, as evident by immunostaining of the AIS structural protein βIV spectrin. AIS shortening occurs in the absence of altered neuronal and AIS protein levels. We found no change in nodes of Ranvier, another neuronal functional domain sharing a molecular organization similar to the AIS. This is the first study to identify AIS alteration in type 2 diabetes condition. Since AIS shortening is known to lower neuronal excitability, our results may provide a new avenue for understanding and treating cognitive and mood impairments in type 2 diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

Type 2 Diabetes Leads to Axon Initial Segment Shortening in db/db Mice

Yermakov

Drouet

Griggs

et al. 2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Various neurotrophic secreted factors released from microglia induce neurite outgrowth and have been shown to be involved in regulating the cytoarchitecture of the developing brain [18][19][20] . Pro-inflammatory microglia, however, up-regulate cytokines and enzymes that produce reactive oxygen species, which have been implicated in axonal injury and disruption [16,[21][22][23][24][25][26][27][28][29][30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

Microglial process convergence on axonal segments in health and disease

Benusa

Lafrenaye

2020

View full text Add to dashboard Cite

Microglia dynamically interact with neurons influencing the development, structure, and function of neuronal networks. Recent studies suggest microglia may also influence neuronal activity by physically interacting with axonal domains responsible for action potential initiation and propagation. However, the nature of these microglial process interactions is not well understood. Microglial-axonal contacts are present early in development and persist through adulthood, implicating microglial interactions in the regulation of axonal integrity in both the developing and mature central nervous system. Moreover, changes in microglial-axonal contact have been described in disease states such as multiple sclerosis (MS) and traumatic brain injury (TBI). Depending on the disease state, there are increased associations with specific axonal segments. In MS, there is enhanced contact with the axon initial segment and node of Ranvier, while, in TBI, microglia alter interactions with axons at the site of injury, as well as at the axon initial segment. In this article, we review the interactions of microglial processes with axonal segments, analyzing their associations with various axonal domains and how these interactions may differ between MS and TBI. Furthermore, we discuss potential functional consequences and molecular mechanisms of these interactions and how these may differ among various types of microglial-axonal interactions.

show abstract

“…Although most pediatric patients diagnosed with Acute Lymphoblastic Leukemia (ALL) have a favorable prognosis, achievement of long-term survival remains a major clinical challenge, particularly at relapse. 1 Alterations of cell death programs cause treatment failure and resistance in many cancers including leukemia. The nuclear phosphoprotein p53 is a transcription factor controlling cellular responses to stress, including DNA-damage.…”

Section: Introductionmentioning

confidence: 99%