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• Mice with a mutation in the Wolfram Syndrome gene Cisd2 , display sonic vocalizations. • Mutants display hypoactivity across several behavioral assays. • Cisd2 mutants have elevated corticosterone. • Mutant mice exhibit lower prepulse inhibition. • Unlike Wolfram Syndrome patients, mutant mice do not have impaired glucose tolerance. Wolfram syndrome (WFS) is a rare autosomal recessive disorder characterized by diabetes mellitus and insipidus, progressive optic atrophy and sensorineural deafness. An increased incidence of psychiatric disorders has also been reported in WFS patients. There are two subtypes of WFS. Type 1 (WFS1) is caused by mutations in the WFS1 gene and type 2 (WFS2) results from mutations in the CISD2 gene. Existing Wfs1 knockout mice exhibit many WFS1 cardinal symptoms including diabetic nephropathy, metabolic disruptions and optic atrophy. Far fewer studies have examined loss of Cisd2 function in mice. We identified B6.DDY- Cisd2m1Lmt, a mouse model with a spontaneous mutation in the Cisd2 gene. B6.DDY- Cisd2m1Lmt mice were initially identified based on the presence of audible sonic vocalizations as well as decreased body size and weight compared to unaffected wildtype littermates. Although Wfs1 knockout mice have been characterized for numerous behavioral phenotypes, similar studies have been lacking for Cisd2 mutant mice. We tested B6.DDY- Cisd2m1Lmt mice in a battery of behavioral assays that model phenotypes related to neurological and psychiatric disorders including anxiety, sensorimotor gating, stress response, social interaction and learning and memory. B6.DDY- Cisd2m1Lmt mice displayed hypoactivity across several behavioral tests, exhibited increased stress response and had deficits in spatial learning and memory and sensorimotor gating compared to wildtype littermates. Our data indicate that the B6.DDY- Cisd2m1Lmt mouse strain is a useful model to investigate potential mechanisms underlying the neurological and psychiatric symptoms observed in WFS. [ABSTRACT FROM AUTHOR]