Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients

Abstract

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. 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. 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. 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.