Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS) and the major cause of non-traumatic neurological disability in young adults in the USA. The classical view of MS as a white matter disease has recently been extended to include gray matter demyelination. The clinical impact of gray matter demyelination may explain why white matter lesions detected by brain imaging poorly correlate with neurological disability in MS patients. Greater than 50% of MS patients are cognitively impaired and their cognitive dysfunction has a greater impact on quality of life than physical disability. Recent studies of postmortem MS brains have established that hippocampal demyelination disrupts the maintenance of excitatory synapses and activation of neuronal signaling cascades that modulate memory and learning. Hippocampal demyelination is a likely cause of cognitive decline in MS patients. To confirm and extend this hypothesis, we have successfully developed a mouse model of hippocampal demyelination and established that these mice have reduced memory/learning, reduced synaptic densities, reduced neuronal proteins that modulate memory/learning and reduced long term potentiation (LTP). Remyelination reversed these changes. The studies outlined in this proposal are designed to unravel the sequence of neuronal changes in demyelinated hippocampi that contribute to neuronal dysfunction and memory impairment. We utilize a multidisciplinary approach to correlate behavioral, electrophysiological, biochemical, morphological, and in vivo imaging changes in demyelinated hippocampi and will determine if remyelination reverses documented changes. Our studies are translational and should identify potential therapeutic targets that could reduce or delay cognitive decline in MS patients. Our mouse model should also provide a platform for """"""""proof of principle"""""""" testing of therapies designed to improve cognition in MS patients.

Public Health Relevance

Cognitive decline is common in over 50% of individuals with multiple sclerosis and has a greater impact on quality of life and unemployment than physical disability. Analyses of postmortem MS brains have identified hippocampal demyelination as a possible cause of cognitive decline in MS patients. To date animal models of hippocampal demyelination have not been available. We have developed a reliable animal model of hippocampal demyelination and show that many of the neuronal changes described in demyelinated hippocampi in MS brain also occur in our mice. We will use a multidisciplinary approach to dissect neuronal changes that are responsible for memory loss caused by hippocampal demyelination.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Utz, Ursula
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Bai, C Brian; Sun, Sunny; Roholt, Andrew et al. (2016) A mouse model for testing remyelinating therapies. Exp Neurol 283:330-40
Dutta, Ranjan; Chomyk, Anthony M; Chang, Ansi et al. (2013) Hippocampal demyelination and memory dysfunction are associated with increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors. Ann Neurol 73:637-45