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

Abstract

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.

Catalpol as a Component of Rehmannia glutinosa Protects Spinal Cord Injury by Inhibiting Endoplasmic Reticulum Stress-Mediated Neuronal Apoptosis

“…As an axonal membrane protein, GAP43 is involved in the extracellular growth and regeneration of nerve cells in vivo. It is abundantly expressed during the regeneration and development of neurons during injury (Zhu et al, 2020b;Kim et al, 2021). MAP-2 contributes to the building of the neuronal cytoskeleton at every stage of the nervous system (Subbarayan et al, 2020;Zhou et al, 2021).…”

1,800 MHz Radiofrequency Electromagnetic Irradiation Impairs Neurite Outgrowth With a Decrease in Rap1-GTP in Primary Mouse Hippocampal Neurons and Neuro2a Cells

“…Neurite outgrowth plays a key role in the formation of neural networks during neural development and nerve regeneration after trauma or disease. Neurite outgrowth is regulated by precise signal networks that control processes from sprouting and extending to the formation of axons and dendrites ( 38 , 39 ). Abnormal neurite outgrowth may cause aberrant polarity, abnormal synaptic plasticity of neuronal cells, and damage to axons and dendrites.…”

Therapeutic mechanism of transcranial iTBS on nerve regeneration and functional recovery in rats with complete spinal cord transection

“…It is highly abundant in the dynamic structure of the presynaptic membrane and growth cone. Changes in synaptic morphology are caused by neuronal differentiation during nervous system development, and nerve ber regeneration and neural repair after injury can lead to the increased expression of GAP43 [25] . Noticeably, compared with the Control and sham iTBS groups, the iTBS group showed that the area of GAP43 + nerve bers was increased after four weeks of SCI (Fig.…”