Metabolic profile and cognitive abilities of eIF2B mutant mouse models for VWM Disease

Eukaryotic translation initiation factor 2B (eIF2B) is a master regulator of protein synthesis under normal and stress conditions. Mutation in any of the five genes encoding eIF2B subunits lead to vanishing white matter disease (VWMD), a recessive neurodegenerative cure-less pathological condition, which exhibits progressive loss of CNS myelin, motor and neurological deficits, followed by early death. The first animal model for the disease, eIF2B5^R132H/R132H mice, exhibit delayed development of brain white matter and mild dysfunction in motor performance. To further study the disease we developed an additional mouse model, eIF2B5^E646K/E646K mice. Time-course brain MRI revealed impairments in hippocampus development, which is in-line with the cognitive deficiency associated with VWMD patients. Previous studies using primary MEFs and astrocytes isolated from eIF2B5^R132H/R132H mice demonstrated impaired mitochondrial oxidative phosphorylation (OXPHOS) associated with a compensatory increase in mitochondria abundance. While the compensation is sufficient for the energetic requirements of MEFs, it is not sufficient for astrocytes, explaining the major involvement of astrocytes in the disease. Further characterization of the metabolic phenotype using metabolic cages to characterize the metabolic profile of the two animal models will be shown. The metabolic rate of the whole animals within the thermoneutral zone and upon increased ambient temperatures will be demonstrated. In addition, in-vivo test of hippocampal-dependent learning and long-term memory will be presented, with emphasis on discrimination and reversal learning abilities in WT and eIF2B-mutant mice.