ROLE OF L-LACTATE AND AMP-ACTIVATED PROTEIN KINASE IN ENHANCED FEAR MEMORY IN DIABETIC MICE

Abstract Aim & Objectives The prevalence of mental disorder including depression and anxiety is higher in patients with diabetes mellitus than in the general population, but it is unclear how diabetes mellitus causes mental disorder. Because several studies suggest that hyperglycemia affects brain function, the present study investigated the role of L-lactate, which is produced from glucose in the brain, in enhanced fear memory in diabetic mice. In addition, it has been reported that L-lactate inhibits AMP- activated protein kinase (AMPK). Thus, we also examined whether AMPK in the brain is involved in enhanced fear memory in diabetic mice. Method Male ICR mice were used. Diabetes was induced by streptozotocin, with experiments conducted 2 weeks after streptozotocin injection. Fear memory was measured by the conditioned fear test. Protein levels of AMP-activated protein kinase (AMPK) and phosphorylated AMPK in the amygdala and hippocampus, which are thought to be involved in fear memory, were measured by Western blot. Results Diabetic mice showed a longer duration of freezing than control mice. In diabetic mice, L-lactate level was increased in the amygdala and hippocampus. I.c.v. injection of L-lactate into non-diabetic mice increased duration of freezing. In addition, i.c.v. injection of L-lactate into non-diabetic mice significantly decreased the protein level of phosphorylated AMPK, which is an active form of AMPK, in the hippocampus. Increase in duration of freezing induced by L-lactate was inhibited by the AMPK activator AICAR. The protein level of phosphorylated AMPK was decreased in the amygdala and hippocampus of diabetic mice. I.c.v. injection of AMPK inhibitor compound C into non-diabetic mice increased duration of freezing, whereas i.c.v. injection of AICAR inhibited the increased duration of freezing in diabetic mice. Finally, the AMPA receptor antagonist NBQX inhibited the increased duration of freezing following i.c.v. injection of L-lactate or compound C and the same injection also inhibited the increased duration of freezing in diabetic mice. Discussion & Conclusion Our results indicate that fear memory is enhanced in diabetic mice. In addition, it appears that increase in L-lactate production, possibly from plasma glucose in the amygdala and hippocampus, plays a key role in enhanced fear memory in diabetic mice. Moreover, increase in L-lactate in the amygdala and hippocampus inhibits AMPK activity, which enhances fear memory in diabetic mice possibly through activation of glutamate neurons and/or AMPA receptor function.