Kir6.1 Heterozygous Mice Exhibit Aberrant Amygdala-Dependent Cued Fear Memory

ATP-sensitive K⁺ (K_ATP) channels are predominantly expressed in the brain and consist of four identical inward-rectifier potassium ion channel subunits (Kir6.1 or Kir6.2) and four identical high-affinity sulfonylurea receptor subunits (SUR1, SUR2A, or SUR2B). We previously observed that chronic corticosterone-treated (CORT) mice exhibited enhanced anxiety-like behaviors and cued fear memory. In the present study, the protein and mRNA expression levels of Kir6.1, but not Kir6.2, were decreased in the lateral amygdala (LA) of CORT mice. Heterozygous Kir6.1-null (Kir6.1^+/-) mice also showed enhanced tone (cued) fear memory and long-term potentiation (LTP) in the cortico-LA pathway compared to those in wild-type mice. However, LTP was not enhanced in the hippocampal CA1 regions of Kir6.1^+/- mice. Consistent with increased cued fear memory, both Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) activities were significantly elevated in the LAs of Kir6.1^+/- mice after tone stimulation. Our results indicate that increased CaMKII and ERK activities may induce LTP in the LA in Kir6.1^+/- mice, leading to aberrant cued fear memory. The changes in neural plasticity in the LA of Kir6.1^+/- mice were associated with anxiety-like behaviors and may be related to the pathogenic mechanisms of anxiety disorders in human patients.