Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a novel mouse model of Snyder-Robinson Syndrome

Polyamines (putrescine, spermidine, and spermine) are essential for cellular growth and are subject to strict metabolic regulation. Mutations in the gene encoding spermine synthase (SMS) lead to the accumulation of spermidine and an X-linked recessive disorder known as Snyder-Robinson syndrome (SRS). There are no treatments available for this rare disease that manifests as mental retardation, thin habitus, and low muscle tone. The development of therapeutic interventions for SRS will require a suitable disease-specific animal model that recapitulates many of the abnormalities observed in these patients. Here, we characterize the molecular, behavioral, and neuroanatomical features of a mouse model with a missense mutation in Sms that results in a glycine-to-serine substitution at position 56 (G56S) of the SMS protein. Mice harboring this mutation exhibited a complete loss of SMS protein and elevated spermidine/spermine ratios in skeletal muscles and the brain. In addition, the G56S mice demonstrated increased anxiety, impaired learning, and decreased explorative behavior in fear conditioning, Morris water maze, and open field tests, respectively. Furthermore, the mice undergo significant reductions in body weight over time, as well as abnormalities in brain structure and bone density. Transcriptomic analysis of the cerebral cortex revealed downregulation of genes associated with mitochondrial oxidative phosphorylation and synthesis of ribosomal proteins. Our findings also revealed impaired mitochondrial bioenergetics in fibroblasts isolated from the G56S mice, which provides a link between these processes and the pathogenesis of SRS. Collectively, our findings establish the first in-depth characterization of SRS-associated mechanisms in a preclinical animal model and identify cellular processes that can be targeted for future therapeutic development. ### Competing Interest Statement The authors have declared no competing interest.