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

Ilknur Özen, Hongcheng Mai, Alessandro De Maio, Karsten Ruscher, Georgios Michalettos, Fredrik Clausen, Michael Gottschalk, Saema Ansar, Sertan Arkan, Ali Erturk, Niklas Marklund

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number129
Pages (from-to)1-15
JournalActa Neuropathologica Communications
Publication statusPublished - 2022

Subject classification (UKÄ)

  • Neurosciences
  • Neurology

Free keywords

  • Axonal injury
  • Central (midline) fluid percussion
  • Cerebellum
  • Demyelination
  • Purkinje cell
  • Traumatic brain injury (TBI)
  • vDISCO


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