Unraveling epigenetic mechanisms causing cognitive dysfunction in experimental diabetes

Abstract Epigenetic mechanisms related to diabetes-afflicted CNS complications are largely unknown. The present study investigated the role of epigenetic mechanisms causing cognitive dysfunction in the Type 1 and 2 diabetic encephalopathy mice model. Dynamic changes in diabetic parameters like fasting blood glucose levels, glucose tolerance tests, and insulin levels were observed after the induction of diabetes. Cognitive functions were significantly diminished in T1D and T2D mice examined by the Morris water maze, novel object recognition test, and Y Maze. Histone profiling revealed a significant reduction in H3 and H4 acetylation in the cortex and hippocampus of T1D and T2D mice vs Controls. While histone deacetylase (HDAC) activity was significantly elevated in brain regions of T1D and T2D mice, the histone acetyltransferase (HAT) activity remained unchanged. Significantly increased HDAC 2, HDAC 3, and HDAC 4 protein and mRNA expression observed in T1D and T2D brain regions may corroborate for increased HDAC activity. No significant change was observed in protein and mRNA expression of HDAC 1, 5, 6, and 7 in diabetic brains. Reduced H3 and H4 acetylation paralleled transcriptional repression of memory-related markers BDNF, SYP, and Psd-95 in the cortex and hippocampus of T1D and T2D. Pharmacological inhibition of HDAC activity by Trichostatin A restored the cognitive changes observed in T1D and T2D. The present study provides a better insight into molecular mechanisms related to diabetes-dependent memory changes that can help to generate new advances for therapeutics to be developed in this area.