Despite recent interest in hippocampal pathology in MS patients, the molecular basis of memory dysfunction in MS has not been investigated. Our data establish that hippocampal demyelination leads to decreased expression of neuronal proteins involved in axonal transport, synaptic plasticity, glutamate homeostasis, memory/learning and neuronal survival. Surprisingly, very few of the neuronal gene products altered in demyelinated MS hippocampus were altered in demyelinated MS motor cortex. Memory dysfunction and hippocampal demyelination are common in MS patients. Our studies therefore provide a molecular basis for memory decline found in individuals with MS and establish that myelination modulates neuronal gene expression in a manner that reflects the specialized functions of different neuronal populations.
Our studies are consistent with previous pathological studies that have documented hippocampal demyelination in postmortem MS brain 8,9
. This includes the overall incidence of hippocampal demyelination and decreases in synaptic terminals. Our approach differs from previous studies as it includes a molecular comparison of myelinated and completely demyelinated hippocampi. Hippocampi were obtained from chronic patients with an average disease duration of 26.6 years. The retention of 80 – 90% of neuronal perikarya in these demyelinated hippocampi is encouraging, as it identifies the demyelinated hippocampal neuron as a viable and abundant therapeutic target. In contrast to AD patients, who are diagnosed at late and possibly irreversible stages of cognitive decline, more than 50% of MS patients are diagnosed in the 3rd
decade of life. MS, therefore, may be the disease of choice for testing therapies that prevent memory decline. Hence, it was important to identify the molecular and cellular changes that accompany hippocampal demyelination. We have identified therapeutic targets that could enhance memory function in MS patients.
Neurogenesis in the adult hippocampus and its possible role in synaptic plasticity has been proposed in various neurological disorders including AD, epilepsy, depression and Parkinson’s disease 31,32
. While we recently provided evidence for neurogenesis in chronic white matter lesions in MS brains 33
, neurogenesis in MS hippocampus has not been investigated. Correlation of cognitive dysfunction demyelination and neurogenesis in MS hippocampus would require development of non-invasive imaging techniques that detect new neurons and demyelinated hippocampi. Conventional brain imaging techniques cannot distinguish myelinated and demyelinated hippocampi, so there is no data on when hippocampi demyelinate during the clinical course of MS. Most of the MS patients who donated brains to the present studies were cognitively impaired, but not tested for memory deficits. Since most of our data were derived from individuals with long disease duration, it is impossible to distinguish primary from secondary changes by analysis of postmortem brains. Data from acute demyelination of the mouse hippocampi will therefore, provided valuable insight into the primary effects of hippocampal demyelination on neuronal protein expression. The neuronal gene with the greatest decrease in demyelinated MS hippocampus was KIF1A, the major molecular motor for anterograde transport of synaptic vesicles to the pre-synaptic terminal. Reduced synaptic vesicle transport and subsequent decreased synaptic firing could account for the majority of gene changes detected in demyelinated post-synaptic hippocampal neurons. In support of this hypothesis, KIF1A mutants show motor and sensory disturbances with significant decreases in synaptic vesicle density, neuronal afferent stimulation and glutamate neurotransmission 23
. The major regulators of synaptic glutamate, astrocytic EAAT 1 and 2, were significantly reduced in demyelinated hippocampi despite astrocytosis. Since increased extracellular glutamate is detrimental to neuronal survival and function, future therapeutic approaches to normalize extracellular glutamate levels in demyelinated hippocampi may partially delay or reverse cognitive decline in MS patients.
In summary, we describe molecular alterations in demyelinated hippocampal neurons that are known to cause memory dysfunction in experimental animal models. The incidence of memory impairment in MS patients is reported to be over 30%. Advances in imaging hippocampal changes in living MS patients will increase our understanding of the incidence and dynamics of hippocampal pathology and will set the stage for the development of reliable surrogate markers for demonstrating the efficacy of future therapies to reduce memory decline in MS patients. The data presented here identify several molecular targets for such therapies.