Therapeutic Testosterone Administration Preserves Excitatory Synaptic Transmission in the Hippocampus during Autoimmune Demyelinating Disease
Autor: | Andrea A Avedisian, Rhonda R. Voskuhl, Marina O Ziehn, Shannon M Dervin, Elizabeth Umeda, Thomas J. O'Dell |
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Rok vydání: | 2012 |
Předmět: |
Male
Polyradiculoneuropathy Hippocampus Therapeutic testosterone Biology Neurotransmission Synaptic Transmission Article Mice Random Allocation Postsynaptic potential medicine Animals Testosterone Drug Implants General Neuroscience Experimental autoimmune encephalomyelitis Excitatory Postsynaptic Potentials Membrane Proteins medicine.disease Mice Inbred C57BL nervous system Synaptic plasticity Excitatory postsynaptic potential Disks Large Homolog 4 Protein Guanylate Kinases Postsynaptic density Neuroscience |
Zdroj: | The Journal of Neuroscience. 32:12312-12324 |
ISSN: | 1529-2401 0270-6474 |
DOI: | 10.1523/jneurosci.2796-12.2012 |
Popis: | Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in over 30% of these patients. While post-mortem pathology studies and in vivo magnetic resonance imaging (MRI) demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (post-disease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal cornu ammonis 1 (CA1), decreased pre (Synapsin-1) and post (postsynaptic density 95; PSD-95) synaptic staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as pre- and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in excitatory postsynaptic potentials are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE. This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal function and disease-associated pathology that occur during autoimmune disease. |
Databáze: | OpenAIRE |
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