An Electrophysiological Model of Spinal Transmission Deficits in Mouse Experimental Autoimmune Encephalomyelitis

Hanák, S; Reilly, Erin M.; Wotanis, Jill; Zhu, Bin; Pulicicchio, Claudine; McMonagle-Strucko, Kathleen; Wettstein, Joseph G.; Black, Mark D.

doi:10.1124/jpet.103.056994

Cited by 4 publications

(4 citation statements)

References 40 publications

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“…Furthermore, microglial activation was directly correlated with deficits in excitatory postsynaptic transmission. Our findings are consistent with previous reports that activated microglia in the hippocampus in non-EAE conditions contribute to synaptic stripping (Schafer et al, 2010) and impaired synaptic transmission (Hanak et al, 2004). …”

Section: Discussionsupporting

confidence: 93%

Therapeutic Testosterone Administration Preserves Excitatory Synaptic Transmission in the Hippocampus during Autoimmune Demyelinating Disease

et al. 2012

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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.

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Section: Discussionsupporting

confidence: 93%

Therapeutic Testosterone Administration Preserves Excitatory Synaptic Transmission in the Hippocampus during Autoimmune Demyelinating Disease

et al. 2012

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“…In order to utilize multivariate analysis and determine the relationship between the neurological deficit patterns and the SSEPs, the experimental design would have required group sizes much larger than those used in this study. In PLP-induced EAE in SJL/J mice, animals experiencing repeated cycles of relapse and remission exhibit more significant deficits in veratridine-stimulated spinal cord transmission than mice displaying few relapses [17]. In this study, axonal loss and demyelination occurred in the 25-80 % range, while inflammation occurred between 5-25 %.…”

Section: Discussionmentioning

confidence: 91%

Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis

et al. 2009

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Teriflunomide is an orally available anti-inflammatory drug that prevents T and B cell proliferation and function by inhibition of dihydroorotate dehydrogenase. It is currently being developed for the treatment of multiple sclerosis (MS). We report here for the first time the anti-inflammatory effects of teriflunomide in the Dark Agouti rat model of experimental autoimmune encephalomyelitis (EAE). Neurological evaluation demonstrated that prophylactic dosing of teriflunomide at 3 and 10 mg/kg delayed disease onset and reduced maximal and cumulative scores. Therapeutic administration of teriflunomide at doses of 3 or 10 mg/kg at disease onset significantly reduced maximal and cumulative disease scores as compared to vehicle treated rats. Dosing teriflunomide at disease remission, at 3 and 10 mg/kg, reduced the cumulative scores for the remaining course of the disease. Teriflunomide at 10 mg/kg significantly reduced inflammation, demyelination, and axonal loss when dosed prophylactically or therapeutically. In electrophysiological somatosensory evoked potential studies, therapeutic administration of teriflunomide, at the onset of disease, prevented both a decrease in waveform amplitude and an increase in the latency to waveform initiation in EAE animals compared to vehicle. Therapeutic dosing with teriflunomide at disease remission prevented a decrease in evoked potential amplitude, prevented an increase in latency, and enhanced recovery time within the CNS.

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“…30 Finally, at the electrophysiological level, motor and sensory transmission defects in SJ/L mice corresponded with the appearance of neurological deficits and occurred in both the inflammatory period of the acute attack as well as in the chronic demyelinating stages. 31 This study indicated that defects in synaptic function, and not solely demyelination, resulted in clinical symptoms. Our study showing that loss of YFP fluorescence parallels the onset of clinical disease and inflammation are in accordance with the above studies, which collectively demonstrate that altered neuronal function correlates with the appearance of neurological disease.…”

Section: Discussionmentioning

confidence: 99%

T-Cell-Mediated Disruption of the Neuronal Microtubule Network

Shriver

Dittel

2006

The American Journal of Pathology

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During the course of the central nervous system autoimmune disease multiple sclerosis (MS), damage to myelin leads to neurological deficits attributable to demyelination and conduction failure. However, accumulating evidence has indicated that axonal injury is also a predictor of MS clinical disease. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we examined whether axonal dysfunction occurred early in disease and correlated with disease symptoms. We tracked axons during EAE by using transgenic mice that express yellow fluorescent protein (YFP) in neurons. At the onset of disease, we observed a loss of YFP fluorescence in the spinal cord in areas that coincided with immune cell infiltration, before prominent demyelination. These inflammatory lesions also exhibited evidence of axonal injury but not axonal loss. During the recovery phase of EAE, the return of YFP fluorescence occurred in parallel with the resolution of inflammation. Using in vitro cultured neurons expressing YFP, we demonstrated that encephalitogenic T cells alone directed the destabilization of microtubules within neurites , resulting in a change in the pattern of YFP fluorescence. This study provides evidence that encephalitogenic T cells directly cause reversible axonal dysfunction at the onset of neurological deficits during an acute central nervous system inflammatory attack.

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An Electrophysiological Model of Spinal Transmission Deficits in Mouse Experimental Autoimmune Encephalomyelitis

Cited by 4 publications

References 40 publications

Therapeutic Testosterone Administration Preserves Excitatory Synaptic Transmission in the Hippocampus during Autoimmune Demyelinating Disease

Therapeutic Testosterone Administration Preserves Excitatory Synaptic Transmission in the Hippocampus during Autoimmune Demyelinating Disease

Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the Dark Agouti rat model of experimental autoimmune encephalomyelitis

T-Cell-Mediated Disruption of the Neuronal Microtubule Network

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