Remyelinating therapy reverses neuronal activity suppression in a mouse model of demyelination

Central nervous system demyelination contributes to disability in disorders such as multiple sclerosis, yet how myelin loss and repair alter neuronal function over time remains poorly understood. We longitudinally monitored hippocampal myelination and CA1 pyramidal neuron activity in the same mice for more than 100 days, spanning cuprizone-induced demyelination and subsequent treatment with clemastine, a clinically investigated remyelinating agent. Imaging-detectable myelin loss emerged only after several weeks, whereas neuronal activity declined within days, indicating that circuit dysfunction precedes myelin degeneration. Neuronal activity also exhibited sex-dependent biphasic trajectory, with greater early deficits in females and later deficits in males. Clemastine promoted axonal myelination and restored neuronal activity to pre-cuprizone levels. Longitudinal tracking of individual neurons across baseline, demyelination, and treatment further showed that recovery depended on cellular baseline properties: more active neurons exhibited larger declines during vehicle treatment and larger increases during clemastine treatment. Together, these findings identify sex-dependent neuronal responses to demyelination, link structural myelin repair with functional circuit recovery, and highlight heterogeneity in neuronal recovery associated with baseline activity, supporting the use of functional outcomes to evaluate candidate remyelination therapies.