Axonal/neuronal pathology is an important and early feature of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the underlying molecular mechanisms remain elusive. We have previously reported that the levels of an important neuronal calcium pump, plasma membrane calcium ATPase 2 and synaptic proteins, synapsin IIa and syntaxin 1B are decreased in the rat spinal cord at onset of acute EAE. Whether the expression of these genes is restored during neurological recovery and affected in other EAE models is currently unknown. The present study was undertaken to address these issues by use of validated multiplex quantitative real-time RT-PCR with fluoro-primers, western blot and immunocytochemistry. We report that plasma membrane calcium ATPase 2 (PMCA2) transcript and protein levels return to control values during recovery from acute disease in the Lewis rat, whereas they are reduced throughout the course of chronic, non-remitting EAE in the C57Bl/6 mouse. These results indicate a close correlation between PMCA2 levels and disease course as defined by clinical scores reflecting motor deficits. Decrease in synapsin IIa expression also correlated with the onset and progression of neurological symptoms, whereas the pattern of syntaxin 1B mRNA and protein expression suggested post-transcriptional regulation. The decrease in PMCA2 transcript and protein levels and the correlation between expression and disease course in two different EAE models further highlight the importance of this calcium pump in neuronal dysfunction during inflammation.