Traumatic brain injury-induced hypo-O-GlcNAcylation contributes to cognitive dysfunction in adult zebrafish

다국어 초록 (Multilingual Abstract)

Traumatic brain injury (TBI) is known as a functional corruption of the brain caused by a bump or blast to the head when an object hits suddenly or pierces the skull and penetrates brain tissues. There is an urgent need of understanding the pathophysiology following TBI because the morbidity and mortality rates worldwide caused by TBI have remained high throughout decades. In this study, we used a novel model of adult zebrafish to study the molecular and physiological changes following TBI. Using T-maze, on the 3rd-day post-stab-lesion injury (dpi), learning and memory deficits and poor social response were observed. Results from mirror biting and novel tank tests also provided us insight into their defective mobility, explorational, and territorial instincts. Neurogenesis impairment and severe brain inflammation were also altered following TBI, especially at 3 dpi. Upon injury, a notable decrease of O-GlcNAc level was remarked at 3dpi. Deregulation of O-GlcNAcylation which led to impaired glucose metabolism was informed to contribute to the pathologies of neurodegenerative diseases. Glucosamine (GlcN), a natural compound found in cartilage, is known as a derivative of the pathway that can increase O-GlcNAcylation by bypassing the reaction catalyzed by a rate liming enzyme GFAT. To further investigate the correlation, after TBI exposure, zebrafish had been recovered 3 days in 0.1g/L glucosamine (GlcN) diluted in water. Under the treatment of GlcN, the inflammation level reduced significantly, indicated by the decrease of Nuclear factor-kappa B and Glial fibrillary acidic protein expression in the telencephalon. TBI-induced downregulation of the cAMP signaling pathway and its relevant proteins in synaptic plasticity were rescued by GlcN. O-GlcNAc deficiency observed previously, as well as L/M capability were retrieved. GlcN also elevated the number of new cells regenerations and neuronal differentiation. As a result, regulation of brain O-GlcNAcylation may hold a potential role in TBI’s recuperation.