Behavioural phenotyping of knockout mice for the sigma-1 (σ1) chaperone protein revealed gender-related anxiety, depressive-like and memory alterations

The sigma-1 (sigma(1)) protein regulates calcium homeostasis and acts as an endoplasmic reticulum chaperone. It can be activated by ligands which impact memory, depression, anxiety or addiction processes. We here characterized the behavioural phenotype of knockout (KO) mice for the sigma(1) protein. Two-month old male sigma(-/-)(1) mice showed signs of anxiety in the open-field, passive avoidance or elevated plus-maze test, but other activity or memory responses were unchanged. Female sigma(-/-)(1) mice showed deficits in spontaneous alternation or water-maze learning. Twelve-month old sigma(+/-)(1) female mice showed deficits in alternation and sigma(-/-)(1) mice in avoidance escape latency. Two- and 14-month old female sigma(-/-)(1) mice showed decreased plasma 17 beta-estradiol levels. Treatment with 17 beta-estradiol (0.1, 0.2 mg/kg i.p.) reversed the spatial memory deficits in young and aged mice. Male sigma(1) KO mice showed enhanced response in the forced swimming test. Igmesine, a sigma(1) agonist, failed to decrease immobility in sigma(1) KO mice. Fluoxetine and sertraline were more efficient in sigma(1) KO mice, an effect likely related to their sigma(1) antagonist activity. Imipramine, desipramine and amitriptyline were equally active. sigma(1) Protein invalidation therefore affected stress or anxiety response but not memory in males. Changes in steroid tonus in female animals led, however, to memory impairments that increased with age.