Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient mice

Stress results in alterations in behavior and physiology that can be either adaptive or maladaptive. To define the molecular pathways involved in the response to stress further, we generated mice deficient (KO) in the calcium -stimulated adenylyl cyclase type VIII (AC8) by homologous recombination in embryonic stem cells. AC8 KO mice demonstrate a compromise in calcium-stim ulated AC activity in the hippocampus, hypothalamus, thalamus, and brainste m. Hippocampal slices derived from AC8 KO mice fail to demonstrate CA1-regi on long-term depression after low-frequency stimulation, and AC8 KO mice al so fail to activate CRE-binding protein in the CA1 region after restraint s tress. To define the behavioral consequences of AC8 deficiency, we evaluate d AC8 KO mice in the elevated plus-maze and open field. Although naive AC8 KO mice exhibit indices of anxiety comparable with that of wild-type mice, AC8 KO mice do not show normal increases in behavioral markers of anxiety w hen subjected to repeated stress such as repetitive testing in the plus-maz e or restraint preceding plus-maze testing. These results demonstrate a nov el role for AC8 in the modulation of anxiety.