Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease

Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in >30% of these patients. While postmortem pathology studies and in vivo magnetic resonance imaging demonstrate that the hippocampus is targeted in MS, the ne...

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Bibliographic Details
Published in:The Journal of neuroscience 2012-09, Vol.32 (36), p.12312-12324
Main Authors: Ziehn, Marina O, Avedisian, Andrea A, Dervin, Shannon M, Umeda, Elizabeth A, O'Dell, Thomas J, Voskuhl, Rhonda R
Format: Article
Language:English
Subjects:
Animals
Disks Large Homolog 4 Protein
Drug Implants
Excitatory Postsynaptic Potentials - drug effects
Excitatory Postsynaptic Potentials - physiology
Guanylate Kinases - physiology
Hippocampus - drug effects
Hippocampus - metabolism
Hippocampus - pathology
Male
Membrane Proteins - physiology
Mice
Mice, Inbred C57BL
Polyradiculoneuropathy - drug therapy
Polyradiculoneuropathy - metabolism
Polyradiculoneuropathy - pathology
Random Allocation
Synaptic Transmission - drug effects
Synaptic Transmission - physiology
Testosterone - administration & dosage
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Summary:Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in >30% of these patients. While postmortem pathology studies and in vivo magnetic resonance imaging 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 (postdisease 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 CA1, decreased presynaptic (Synapsin-1) and postsynaptic (postsynaptic density 95; PSD-95) staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as presynaptic and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in EPSPs 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.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/JNEUROSCI.2796-12.2012