Hippocampal CaMKII-α β-hydroxybutyrylation induces memory deficits in mice with type 1 diabetes mellitus

Memory loss is a manifestation of type 1 diabetes mellitus (T1DM)-induced brain damage resulting from hyperglycemia. However, the mechanism underlying T1DM-induced memory deficit remains largely unknown. In diabetes, ketogenesis occurs upon insulin deficiency, and β-hydroxybutyrate (β-OHB) is synthesized and plays a dominant role in diabetic ketoacidosis. In the present study, we investigate the effect of β-OHB-mediated lysine β-hydroxybutyrylation (kbhb) of hippocampal calcium/calmodulin-dependent kinase II-α (CaMKII-α) on memory deficits in male T1DM mice. We find that streptozotocin (STZ) induced a significant increase in the concentration of hippocampal β-OHB in T1DM mice. High β-OHB levels promote CaMKII-α kbhb at the K42 and K267 residues and further inhibit CaMKII activity. The suppression of CaMKII-α kbhb in the hippocampus via the inhibition of P300, a kbhb transferase, reverse the decrease in CaMKII activity and alleviate memory deficits in T1DM mice. Molecular dynamics (MD) simulations further reveale that the enhanced flexibility caused by CaMKII-α kbhb on the critical, conserved residue K42, which alters its side chain, in the catalytic ATP-binding site of this enzyme may be one of the factors responsible for the observed reduction enzymatic activity. Collectively, our results show that a high β-OHB concentration dysregulates hippocampal CaMKII-α kbhb, which may contribute to memory deficits in T1DM mice.