Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) with limited treatment options. Furthermore, progressive neurodegeneration during MS has no approved treatment possibilities yet. The pathogenesis of MS and other neurological disorders includes many processes that either influence Ca2+ or are affected by Ca2+ homeostasis in neurons. Thus, modulation of neuronal Ca2+ homeostasis is an attractive neuroprotective and therapeutic strategy against neurodegenerative disorders. Ca2+ release-activated Ca2+ channels (CRAC), which mediate a store-operated calcium entry (SOCE), are the most recently identified Ca2+ channel family. Their specific roles in Ca2+ homeostasis and cell function are not completely described, especially in neurons. SOCE contributes to neuronal damage under hypoxia and can influence mitochondria function and synaptic stability. In this work, it was shown for the first time that neuronal SOCE contributes to the pathological processes during CNS inflammation using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Experiments with a neuron-specific deletion of the Stim1 and Stim2 showed a protective role of SOCE genetic deletion during EAE while genetic deletion of the Orai2 in neurons had no effect. Further analysis of the animals with Stim1 and Stim2 neuron-specific deletion show unexpected phenotype in vivo (including hyperactivity, exploratory deficits, and reduced long-term life expectancy) and in vitro (including effective Ca2+ level and neuronal network activity). Altogether, this work reveals that neuronal SOCE plays an essential role in neuronal network excitability and has a systemic effect on mice The data generated within the scope of this work is of great scientific interest in the context of inflammatory neurodegenerative disorders like MS and could be used to further develop novel treatment strategies against neurodegeneration.