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Published on: March 1, 2017
Disturbed Presynaptic Ca2+ Signaling in Photoreceptors in the EAE Mouse Model of Multiple Sclerosis
Amrita Mukherjee1, Rashmi Katiyar1, Ekta Dembla1
1Institute of Anatomy and Cell Biology, Department of Neuroanatomy, Saarland University, Medical School, 66421 Homburg, Germany.
Abstract:
Multiple sclerosis (MS) is a demyelinating disease caused by an auto-reactive immune system. Recent studies also demonstrated synapse dysfunctions in MS patients and MS mouse models. We previously observed decreased synaptic vesicle exocytosis in photoreceptor synapses in the EAE mouse model of MS at an early, preclinical stage. In the present study, we analyzed whether synaptic defects are associated with altered presynaptic Ca2+ signaling. Using high-resolution immunolabeling, we found a reduced signal intensity of Cav-channels and RIM2 at active zones in early, preclinical EAE. In line with these morphological alterations, depolarization-evoked increases of presynaptic Ca2+ were significantly smaller. In contrast, basal presynaptic Ca2+ was elevated. We observed a decreased expression of Na+/K+-ATPase and plasma membrane Ca2+ ATPase 2 (PMCA2), but not PMCA1, in photoreceptor terminals of EAE mice that could contribute to elevated basal Ca2+. Thus, complex Ca2+ signaling alterations contribute to synaptic dysfunctions in photoreceptors in early EAE.
Insights
Multiple sclerosis (MS) causes synaptic defects in photoreceptors, indicated by altered calcium (Ca2+) signaling. Early MS models show reduced calcium channel activity and elevated basal calcium, contributing to visual dysfunction.
Area of Science:
- Neuroscience
- Immunology
- Ophthalmology
Background:
- Multiple sclerosis (MS) is an autoimmune demyelinating disease.
- Synapse dysfunction is increasingly recognized in MS, affecting neuronal communication.
- Previous work showed reduced synaptic vesicle exocytosis in photoreceptors during early MS models.
Purpose of the Study:
- To investigate if synaptic defects in early MS are linked to presynaptic calcium (Ca2+) signaling alterations.
- To analyze changes in Ca2+ channels and transporters in photoreceptor terminals during the preclinical stage of experimental autoimmune encephalomyelitis (EAE).
Main Methods:
- High-resolution immunolabeling to assess protein expression at active zones.
- Measurement of depolarization-evoked and basal presynaptic Ca2+ levels.
- Analysis of Na+/K+-ATPase and Ca2+ ATPase (PMCA) expression in photoreceptor terminals.
Main Results:
- Reduced signal intensity of Ca2+ channels (Cav) and RIM2 at active zones in early EAE.
- Significantly smaller depolarization-evoked increases in presynaptic Ca2+.
- Elevated basal presynaptic Ca2+ levels.
- Decreased expression of Na+/K+-ATPase and PMCA2, but not PMCA1, in photoreceptor terminals.
Conclusions:
- Complex alterations in presynaptic Ca2+ signaling, including impaired influx and elevated basal levels, occur in photoreceptors during early EAE.
- These Ca2+ dysregulations contribute to synaptic dysfunction in the context of MS.
- Findings highlight early synaptic pathology in visual pathways during MS.
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