Impaired recognition memory in male mice with a supernumerary X chromosome.

Several aberrant chromosomal constellations are known in men. Of these the karyotype XXY (Klinefelter syndrome, KS) is the most common chromosomal disorder with a prevalence of about one in 800 live-born boys. KS is associated with hypogonadism and is suspected to cause variable physical, physiological and cognitive abnormalities. As a supernumerary X chromosome is also associated with infertility, sound animal models for KS are difficult to obtain. In this study, male mice with two X chromosomes (XXYlow asterisk) were derived from fathers carrying a structurally rearranged Y chromosome (Ylow asterisk) that resulted in physical attachment of a part of the Y chromosome to one X. These animals display certain physiological features that resemble closely those of human KS and can also be utilized to study X chromosomal imbalance and cognition. Therefore 15 XXYlow asterisk males and 15 XYlow asterisk controls were subjected to a battery of behavioral tests, including a general health check, analysis of spontaneous exploration and locomotor activity, measures for anxiety-related behavior and the “novel object task” to test memory performance. Physiologically, XYlow asterisk males did not differ from C57Bl/6 wild type mice carrying a normal Y chromosome, which provided a valid control group. All mice appeared healthy. XXYlow asterisk mice did not differ from their wild type littermates with respect to locomotion, exploration and anxiety-related behavior. XXYlow asterisk male mice, however, exhibited no significant recognition memory performance in contrast with wild type XYlow asterisk males that readily fulfilled a given task. These findings support the hypothesis that the presence of a supernumerary X in male mice influences cognitive abilities. We suggest that the altered endocrine state and/or changes in the dosage of X-linked genes in the XXYlow asterisk mouse model affect brain function, in particular those regions responsible for cognition and learning behavior.