Intrathecal delivery of primary progressive MS cerebrospinal fluid induces behavioral deficits and spinal cord pathology in mice

OBJECTIVE: To develop an animal model of primary progressive MS (PPMS) that exhibits characteristic pathology in the cervical spinal cord to better understand underlying disease pathogenesis.

BACKGROUND: PPMS is characterized by unremitting disease progression and is usually associated with predominant cervical cord disease as determined by MRI imaging. By comparison to other types of MS the number of brain lesions are fewer and do not correlate with disability in PPMS. Therapies targeting the immune system do not halt disease progression in PPMS patients, suggesting that inflammation may not be the predominant contributor to PPMS pathophysiology. Indeed, PPMS lesions tend to contain fewer inflammatory cells. To better understand PPMS we sought to develop a representative disease model in the cervical cord of mice.

DESIGN/METHODS: Cerebrospinal fluid (CSF) obtained from either PPMS or relapsing-remitting (RRMS) patients was administered to mice intrathecally. Control mice received either saline or CSF obtained from healthy individuals. Mice underwent laminectomies at cervical levels 4 and 5, and 3 uls of CSF was injected under the dura mater into the subarachnoid space. Behavioral deficits and pathology were assessed at multiple time points post injection.

RESULTS: Mice injected with PPMS CSF exhibited significantly impaired forelimb function and increased tail flaccidity. Spinal cords from mice injected with PPMS CSF exhibited significantly upregulated GFAP and SMI-32 immunostaining in the dorsal white matter tracts. Microglia activation, as assessed by Iba-1 immunostaining, was similar in all groups. One potential mechanism contributing to this pathology may involve glutamate excitotoxicity since glutamate transporter-1 (GLT-1) was significantly upregulated in PPMS CSF-injected mice. Mice injected with control CSF or saline and those injected with RRMS CSF did not show any changes.

CONCLUSIONS: Intrathecal delivery of PPMS CSF induces motor weakness and is accompanied by reactive astrogliosis, axonal damage and GLT-1 upregulation. This mouse model should enable further investigation of mechanisms underlying PPMS.