Translational behavioral phenotypes in DMSXL mice for CNS manifestations of DM1.

BACKGROUND

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder frequently associated with central nervous system (CNS) involvement, especially in congenital and childhood-onset forms. However, behavioral alterations in preclinical models have so far been only partially characterized, underscoring the need for more comprehensive analyses to support the development of targeted therapeutic approaches.

OBJECTIVE

This study aimed to provide a comprehensive behavioral characterization of DMSXL mice, a transgenic model carrying large CTG repeat expansions in the human DMPK gene, to identify robust and translational CNS-relevant phenotypes for preclinical studies.

METHODS

Using both longitudinal and cross-sectional designs, we assessed a wide range of behavioral domains including motor function, emotional reactivity, cognition, and social interaction over time in DMSXL mice. The study was conducted in two independent laboratories with complementary expertise in DM1 pathophysiology and behavioral phenotyping.

RESULTS

DMSXL mice displayed a consistent pattern of behavioral alterations reflecting CNS dysfunction. These alterations included dysregulation of emotional responses such as altered anxiety-like behavior and impaired risk evaluation, subtle deficits in object recognition and spatial memory, and reduced sociability and social discrimination. Sensorimotor gating and goal-directed behaviors were also affected, while working memory and general locomotion during open field exploration were largely preserved.

CONCLUSIONS

This study defines a constellation of behavioral impairments in DMSXL mice that mirror CNS symptoms in DM1 patients and establishes a set of sensitive, age-dependent endpoints suitable for CNS-targeted therapeutic evaluation. The behavioral framework presented here offers valuable guidance for the design of future preclinical trials in DM1.