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

Özen, Ilknur LU ; Mai, Hongcheng ; De Maio, Alessandro ; Ruscher, Karsten LU ; Michalettos, Georgios LU ; Clausen, Fredrik LU ; Gottschalk, Michael LU orcid ; Ansar, Saema LU ; Arkan, Sertan LU and Erturk, Ali , et al. (2022) In Acta Neuropathologica Communications 10. p.1-15
Abstract

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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Axonal injury, Central (midline) fluid percussion, Cerebellum, Demyelination, Purkinje cell, Traumatic brain injury (TBI), vDISCO
in
Acta Neuropathologica Communications
volume
10
article number
129
pages
1 - 15
publisher
BioMed Central (BMC)
external identifiers
  • pmid:36064443
  • scopus:85137227120
ISSN
2051-5960
DOI
10.1186/s40478-022-01435-3
language
English
LU publication?
yes
additional info
Funding Information: Open access funding provided by Lund University. This work was supported by Swedish Research Council (to NM), Swedish Brain Foundation (to NM and KR), Crafoordska Foundation (to IÖ), Skåne University Hospital ALF funds (to NM and KR), and Hans-Gabriel af Trolle Wachtmeister Foundation (to NM and KR). Publisher Copyright: © 2022, The Author(s).
id
035a8c7a-03f2-43c2-903c-78fcf5239e5e
date added to LUP
2022-10-20 11:03:13
date last changed
2024-04-18 15:50:21
@article{035a8c7a-03f2-43c2-903c-78fcf5239e5e,
  abstract     = {{<p>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.</p>}},
  author       = {{Özen, Ilknur and Mai, Hongcheng and De Maio, Alessandro and Ruscher, Karsten and Michalettos, Georgios and Clausen, Fredrik and Gottschalk, Michael and Ansar, Saema and Arkan, Sertan and Erturk, Ali and Marklund, Niklas}},
  issn         = {{2051-5960}},
  keywords     = {{Axonal injury; Central (midline) fluid percussion; Cerebellum; Demyelination; Purkinje cell; Traumatic brain injury (TBI); vDISCO}},
  language     = {{eng}},
  pages        = {{1--15}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Acta Neuropathologica Communications}},
  title        = {{Purkinje cell vulnerability induced by diffuse traumatic brain injury is linked to disruption of long-range neuronal circuits}},
  url          = {{http://dx.doi.org/10.1186/s40478-022-01435-3}},
  doi          = {{10.1186/s40478-022-01435-3}},
  volume       = {{10}},
  year         = {{2022}},
}