Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients

Objective: Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. Although the clinical impact of gray matter pathology in MS brains is unknown, 30 to 40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investigated in MS patients. Methods: To investigate possible mechanisms of memory impairment in MS patients, we compared morphological and molecular changes in myelinated and demyelinated hippocampi from postmortem MS brains. Results: Demyelinated hippocampi had minimal neuronal loss but significant decreases in synaptic density. Neuronal proteins essential for axonal transport, synaptic plasticity, glutamate neurotransmission, glutamate homeostasis, and memory/learning were significantly decreased in demyelinated hippocampi, but not in demyelinated motor cortices from MS brains. Interpretation: Collectively, these data support hippocampal demyelination as a cause of synaptic alterations in MS patients and establish that the neuronal genes regulated by myelination reflect specific functions of neuronal subpopulations. Ann Neurol 2011;69:445–454