The thrombin receptor modulates astroglia-neuron trophic coupling and neural repair after spinal cord injury

Ha Neui Kim, Erin M. Triplet, Maja Radulovic, Samantha Bouchal, Laurel S. Kleppe, Whitney L. Simon, Hyesook Yoon, Isobel A. Scarisbrick

Research output: Contribution to journalArticlepeer-review


Excessive activation of the thrombin receptor, protease activated receptor 1 (PAR1) is implicated in diverse neuropathologies from neurodegenerative conditions to neurotrauma. PAR1 knockout mice show improved outcomes after experimental spinal cord injury (SCI), however information regarding the underpinning cellular and molecular mechanisms is lacking. Here we demonstrate that genetic blockade of PAR1 in female mice results in improvements in sensorimotor co-ordination after thoracic spinal cord lateral compression injury. We document improved neuron preservation with increases in Synapsin-1 presynaptic proteins and GAP43, a growth cone marker, after a 30 days recovery period. These improvements were coupled to signs of enhanced myelin resiliency and repair, including increases in the number of mature oligodendrocytes, their progenitors and the abundance of myelin basic protein. These significant increases in substrates for neural recovery were accompanied by reduced astrocyte (Serp1) and microglial/monocyte (CD68 and iNOS) pro-inflammatory markers, with coordinate increases in astrocyte (S100A10 and Emp1) and microglial (Arg1) markers reflective of pro-repair activities. Complementary astrocyte-neuron co-culture bioassays suggest astrocytes with PAR1 loss-of-function promote both neuron survival and neurite outgrowth. Additionally, the pro-neurite outgrowth effects of switching off astrocyte PAR1 were blocked by inhibiting TrkB, the high affinity receptor for brain derived neurotrophic factor. Altogether, these studies demonstrate unique modulatory roles for PAR1 in regulating glial-neuron interactions, including the capacity for neurotrophic factor signaling, and underscore its position at neurobiological intersections critical for the response of the CNS to injury and the capacity for regenerative repair and restoration of function.

Original languageEnglish (US)
Pages (from-to)2111-2132
Number of pages22
Issue number9
StatePublished - Sep 2021


  • TrkB
  • astroglia
  • brain derived neurotrophic factor
  • growth cone
  • myelin
  • protease activated receptor 1
  • spinal cord trauma
  • synapse

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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