Disability in multiple sclerosis: When synaptic long-term potentiation fails

• Imaging markers of brain damage and clinical disability are weakly associated in MS.
• Remapping in the cortex of lesioned brain is associated with less disability.
• Synaptic plasticity might provide the biological substrate of cortical remapping.
• Long term synaptic potentiation improves symptoms of neurological defects.
• Synaptic plasticity may limit the clinical expression of brain damage in MS.

Clinical expression of brain damage varies over time and among individuals. This is particularly evident in Multiple Sclerosis (MS) where the expression clinico-radiological paradox has been coined to indicate the weak association between common neuroradiological markers of MS and clinical disability. Here we will review available data suggesting a possible role of adaptive synaptic long-term potentiation (LTP) in the clinical course of MS. We propose that the capacity of the brain to potentiate synaptic excitability in a long-lasting way is the brain's core adaptive property to bridge neuronal damage and clinical expression in multiple sclerosis. LTP, in fact, consists in the strengthening of synaptic communication between two connected neurons, and is virtually able therefore to restore membrane excitability of neurons that have lost part of their synaptic inputs. Recent studies have shown that cortical LTP reserve, explored through transcranial magnetic stimulation (TMS), contrasts disability progression in MS. Furthermore, promotion of cortical LTP through TMS induces acute cortical remapping and ameliorates motor symptoms in MS and in other neurological disorders.