title: Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease.
abstract: Cognitive deficits occur in over half of multiple sclerosis patients, with hippocampal-dependent learning and memory commonly impaired. Data from in vivo MRI and post-mortem studies in MS indicate that the hippocampus is targeted. However, the relationship between structural pathology and dysfunction of the hippocampus in MS remains unclear. Hippocampal neuropathology also occurs in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. Although estrogen treatment of EAE has been shown to be anti-inflammatory and neuroprotective in the spinal cord, it is unknown if estrogen treatment may prevent hippocampal pathology and dysfunction. In the current study we examined excitatory synaptic transmission during EAE and focused on pathological changes in synaptic protein complexes known to orchestrate functional synaptic transmission in the hippocampus. We then determined if estriol, a candidate hormone treatment, was capable of preventing functional changes in synaptic transmission and corresponding hippocampal synaptic pathology. Electrophysiological studies revealed altered excitatory synaptic transmission and paired-pulse facilitation (PPF) during EAE. Neuropathological experiments demonstrated that there were decreased levels of pre- and post-synaptic proteins in the hippocampus, diffuse loss of myelin staining and atrophy of the pyramidal layers of hippocampal cornu ammonis 1 (CA1). Estriol treatment prevented decreases in excitatory synaptic transmission and lessened the effect of EAE on PPF. In addition, estriol treatment prevented several neuropathological alterations that occurred in the hippocampus during EAE. Cross-modality correlations revealed that deficits in excitatory synaptic transmission were significantly correlated with reductions in trans-synaptic protein binding partners known to modulate excitatory synaptic transmission. To our knowledge, this is the first report describing a functional correlate to hippocampal neuropathology in any MS model. Furthermore, a treatment was identified that prevented both deficits in synaptic function and hippocampal neuropathology.
authors.affiliation: Interdepartmental Program of Neuroscience, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Marina O
authors.initials: MO
authors.lastname: Ziehn
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Avedisian
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Dervin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: O'Dell
authors.forename: Rhonda R
authors.initials: RR
authors.lastname: Voskuhl
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D003711:Demyelinating Diseases / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D004964:Estriol / Q000494:pharmacology*; D005260:Female; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006651:Histocytochemistry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C093175:neurexin II; C093438:neuroligin 1; D051528:Guanylate Kinases; D004964:Estriol