Alterations in presynaptic release machinery and synaptic vesicle mobility in the frontal cortex of rats with experimental autoimmune encephalomyelitis

CHANADAY NL; VILCAES AA; DE PAUL AL; TORRES AI,; DEGANO AL; ROTH GA

Washington DC, USA

Congreso; Neuroscience 2014; 2014

Society for Neuroscience

Experimental autoimmune encephalomyelitis (EAE) is an animal model that mimics many of the clinical and pathological features of multiple sclerosis (MS). Both are inflammatory demyelinating and neurodegenerative pathologies of the central nervous system associated with motor, sensory, and cognitive deficits. In MS gray matter atrophy is related to the emergence of cognitive deficits and contributes to clinical progression. However the molecular bases of these changes are still unknown. Taking advantage of EAE similitudes, we herein analyze functional and morphological changes in isolated cortical presynaptic terminals (synaptosomes) from an acute rat model. We show that cortical functional changes during EAE are concentrated at the frontal region and appear concomitantly with the beginning of EAE clinical manifestations, disappearing when animals begin to recover. In this region, nerve terminals exhibit reduced Ca2+-dependent glutamate release, with no changes in total synaptosomal glutamate content. We propose that this is due to a dysfunction in the presynaptic release machinery, mainly synapsin I (SynI) pathway. In this regard, we found reduced basal levels of CaMKIIá associated to synaptic vesicles (SVs) and impaired SynI phosphorylation at site 3 (CaMKIIá substrate) after depolarization. In consequence, SynI fails to detach from SVs. Moreover, our study shows an increase in total and phosphorylated Erk1/2 accompanied by higher basal and stimulated levels of SynI phosphorylated at sites 4/5 (Erk1/2 substrates). This might imply that resting SVs-actin network is more disorganized. Overall, this changes lead to reduced SVs mobility as evidenced by electron microscopy, with no apparent morphological or SVs content differences. These are the first evidences unraveling the molecular pathways involved in neuronal dysfunction in the frontal cortex during EAE. The same mechanisms might be responsible for functional abnormalities in MS and could contribute to the development and progression of cognitive impairments and fatigue.