AMP‐activated protein kinase in the amygdala and hippocampus contributes to enhanced fear memory in diabetic mice

Abstract Background and Purpose Diabetic patients have an increased risk of psychiatric disorders. Because hyperglycaemia increases L‐lactate in the brain and L‐lactate inhibits AMP‐activated protein kinase (AMPK), this study investigated the role of L‐lactate and AMPK in strengthened fear memory, a model for human psychiatric disorders, in diabetic mice. Experimental Approach The diabetic model was mice injected with streptozotocin. Fear memory was measured using the conditioned fear test with low (0.45 mA) or high (0.50 mA) foot shock to cause low and high freezing, respectively. Protein levels of AMPK and phosphorylated AMPK (pAMPK) were measured by western blotting and immunohistochemistry. Key Results At 0.45 mA, the AMPK inhibitor dorsomorphin increased freezing, which was inhibited by the AMPK activator acadesine. In contrast, at 0.50 mA, acadesine decreased freezing, which was inhibited by dorsomorphin. In diabetic mice, pAMPK was decreased in the amygdala and hippocampus. Diabetic mice showed increased freezing at 0.45 mA, which was inhibited by acadesine. In the amygdala and hippocampus, L‐lactate was increased in diabetic mice and injection of L‐lactate into non‐diabetic mice increased freezing at 0.45 mA. In addition, L‐lactate decreased pAMPK in the hippocampus, but not the amygdala, and increase in freezing induced by L‐lactate was inhibited by acadesine. Dorsomorphin‐induced increase in freezing was inhibited by the AMPA receptor antagonist NBQX. Conclusions and Interpretation In diabetic mice, L‐lactate is increased in the amygdala and hippocampus, possibly through hyperglycaemia, which strengthens fear memory through inhibition of AMPK and activation of glutamatergic function.