Diffuse Traumatic Injury in the Mouse Disrupts Axon-Myelin Integrity in the Cerebellum

Özen, Ilknur; Arkan, Sertan; Clausen, Fredrik; Ruscher, Karsten; Marklund, Niklas

doi:10.1089/neu.2021.0321

Cited by 8 publications

(8 citation statements)

References 56 publications

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“…Purkinje cells dysfunction may be associated with axonal swelling during early stage of the injury that precedes demyelination in the cerebellum white matter [ 7 ]. To test this hypothesis, we performed confocal microscopy on Thy1-GFP-M mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous study demonstrated that reduced phosphorylated neurofilament (pNHF) protein levels are correlated with decreased myelin levels in the cerebellum [ 7 ]. To investigate if pathological changes in PCs may be due to myelin loss and reduced pNHF after diffuse TBI, we performed immunohistochemistry on cerebellar sections for MBP and pNHF (SMI-31) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…disruptive processes in the neuronal circuits and the white matter. In response to trauma, these mechanical forces may affect distinct regions in the brain remote from the site of the initial head impacted [ 7 , 26 – 28 ]. The degree of force influencing the cerebellum in our mouse fluid percussion model is not known, while previous work in the lateral fluid percussion model in rats found that the injury resulted in a degree of strain in the cerebellum, albeit at a lower level than other brain regions[ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…In Purkinje cells, progressive myelin loss was associated with extensive axonal changes including axonal swellings and neurofilament dephosphorylation in rat model of chronic, nonimmune-mediated demyelination [ 53 ]. We previously showed that the cFPI model results in progressive myelin loss and axon-myelin disruption in the cerebellum [ 7 ]. Cytosketal disruption can lead to axonal swelling and ultimately to axonal transections resulting in loss of synaptic function.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, patients with cerebellar lesions often show impaired executive function, distorted spatial cognition, and abnormal behaviour [ 6 ]. While the cerebellum may only rarely be directly affected by TBI [ 7 ], ataxia, tremor, and motor deficits may be observed after cortical lesions [ 8 , 9 ], suggesting indirect mechanisms of cerebellar injury. The cerebellum receives the major input from the cerebral cortex via pontine nuclei (PN) that are synaptically intercalated in the cortico-ponto-cerebellar (CPC) pathway.…”

Section: Introductionmentioning

confidence: 99%

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Purkinje cell vulnerability induced by diffuse traumatic brain injury is linked to disruption of long-range neuronal circuits

Özen

Mai

Maio

et al. 2022

acta neuropathol commun

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Cerebellar dysfunction is commonly observed following traumatic brain injury (TBI). While direct impact to the cerebellum by TBI is rare, cerebellar pathology may be caused by indirect injury via cortico-cerebellar pathways. To address the hypothesis that degeneration of Purkinje cells (PCs), which constitute the sole output from the cerebellum, is linked to long-range axonal injury and demyelination, we used the central fluid percussion injury (cFPI) model of widespread traumatic axonal injury in mice. Compared to controls, TBI resulted in early PC loss accompanied by alterations in the size of pinceau synapses and levels of non-phosphorylated neurofilament in PCs. A combination of vDISCO tissue clearing technique and immunohistochemistry for vesicular glutamate transporter type 2 show that diffuse TBI decreased mossy and climbing fiber synapses on PCs. At 2 days post-injury, numerous axonal varicosities were found in the cerebellum supported by fractional anisotropy measurements using 9.4 T MRI. The disruption and demyelination of the cortico-cerebellar circuits was associated with poor performance of brain-injured mice in the beam-walk test. Despite a lack of direct input from the injury site to the cerebellum, these findings argue for novel long-range mechanisms causing Purkinje cell injury that likely contribute to cerebellar dysfunction after TBI.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Purkinje cell vulnerability induced by diffuse traumatic brain injury is linked to disruption of long-range neuronal circuits

Özen

Mai

Maio

et al. 2022

acta neuropathol commun

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Concussion leads to widespread axonal sodium channel loss and disruption of the node of Ranvier

et al. 2022

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Although concussion is a major health concern, little is known about pathophysiological changes that cause post-traumatic cognitive dysfunction. Nonetheless, emerging evidence suggests that selective damage to white matter axons, or diffuse axonal injury (DAI), disrupts brain network connectivity and function. While voltage gated sodium channels (VGSCs) and their anchoring proteins at the nodes of Ranvier (NOR) on axons are key elements of the brain's network signaling machinery, potential changes in their integrity has not been studied in context with DAI. Here, we utilized a well-characterized and clinically relevant swine model of concussion that induces evolving swollen axonal profiles, demonstrated by amyloid precursor protein accumulation (APP) across the white matter. With this model, we found widespread loss of VGSC isoform 1.6 (Nav1.6) concurrent with progressive disruption of NOR cytoskeleton proteins on axons in close proximity, yet distinct from APP+ swollen axonal profiles in the same white matter tracts. Accordingly, these features may represent a unique newfound phenotype of axonal pathology in DAI. These changes persisted 2 weeks after injury and included increases in NOR length and the appearance of amorphous and void nodes as well as heminodes. In addition, there was also a distinct loss in expression of proteins that together serve as major NOR anchoring scaffolds, including βIV-spectrin, ankyrin G, and neurofascin, which were found diffusing into paranodal spaces. Collectively, this widespread and progressive disruption of VGSCs and NOR could have important implications for mechanisms underlying brain network dysfunction after concussion.

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Changes in Noradrenergic Synthesis and Dopamine Beta-Hydroxylase Activity in Response to Oxidative Stress after Iron-induced Brain Injury

Verduzco-Mendoza,

Mota-Rojas,

Olmos-Hernández

et al. 2024

Neurochem Res

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Diffuse Traumatic Injury in the Mouse Disrupts Axon-Myelin Integrity in the Cerebellum

Cited by 8 publications

References 56 publications

Purkinje cell vulnerability induced by diffuse traumatic brain injury is linked to disruption of long-range neuronal circuits

Purkinje cell vulnerability induced by diffuse traumatic brain injury is linked to disruption of long-range neuronal circuits

Concussion leads to widespread axonal sodium channel loss and disruption of the node of Ranvier

Changes in Noradrenergic Synthesis and Dopamine Beta-Hydroxylase Activity in Response to Oxidative Stress after Iron-induced Brain Injury

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