An Examination of the Roles of CX3CR1 and Microglia in a Mouse Model of Degenerative Cervical Myelopathy

Degenerative Cervical Myelopathy (DCM) is the most common form of spinal cord impairmentand is caused by a variety of degenerative or congenital changes in the osseous and soft tissue structures of the spine that result in progressive compression of the cervical spinal cord. DCM can be treated with surgical decompression, but most patients experience residual neurological impairment, and an additional 9% experience persistent decline that may in part be due to secondary injury arising from the effects of surgical decompression. As resident immune cells of the CNS, microglia play significant roles in the response to injury, but they have yet to be investigated after decompression. Further, as a major mediator of microglial activation, CX3CR1 represents a key target to understand and potentially treat secondary injury after decompression. We demonstrate that CX3CR1-signaling and Cx3cr1+ microglia impact immune responses after surgical decompression in a mouse model of DCM by supporting sensorimotor function, mediating synaptic and neuronal preservation, and regulating cytokine production, phagocytosis, and acute vascular leakage after surgery. In this study we developed a novel Tmem119-CreERT2::Cx3cr1- loxP-DTR mouse strain to target Cx3cr1+ microglia after decompression. The parallel use of knock-out and inducible cell ablation models allowed us to establish the primary functions of microglial CX3CR1 signaling in an inflammatory context. These findings coupled with the establishment of novel transgenic tools will contribute to future studies of microglia across neurological conditions. Moreover, by increasing understanding of DCM pathobiology, this work highlights potential therapeutic targets and may aid in the surgical and peri-operative management of DCM.

Department dc:contributor.department

Medical Science

Year dc:date.issued

2024

Author dc:creator

• Brockie, Sydney Tyner Grace

Advisor dc:contributor.advisor

• Fehlings, Michael G

Handle dc:identifier.uri

https://hdl.handle.net/1807/149677

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/149677