Early Neurobehavioral Characterization of the CD Mouse Model of Williams–Beuren Syndrome

Abstract

Williams–Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a chromosomic microdeletion (7q11.23). WBS has been modeled by a mouse line having a complete deletion (CD) of the equivalent mouse locus. This model has been largely used to investigate the etiopathological mechanisms of WBS, although pharmacological therapies have not been identified yet. Surprisingly, CD mice were so far mainly tested in adulthood, despite the developmental nature of WBS and the critical relevance of early timing for potential treatments. Here we provide for the first time a phenotypic characterization of CD mice of both sexes during infancy and adolescence, i.e., between birth and 7 weeks of age. CD pups of both sexes showed reduced body growth, delayed sensory development, and altered patterns of ultrasonic vocalizations and exploratory behaviors. Adolescent CD mice showed reduced locomotion and acoustic startle response, and altered social interaction and communication, the latter being more pronounced in female mice. Juvenile CD mutants of both sexes also displayed reduced brain weight, cortical and hippocampal dendritic length, and spine density. Our findings highlight the critical relevance of early neurobehavioral alterations as biomarkers of WBS pathology, underlying the importance of adolescence for identifying novel therapeutic targets for this neurological disorder.

Serine racemase deletion alters adolescent social behavior and whole-brain cFos activation

“…There was an increase in connectivity in the default-mode network and a decrease in the salience network in the SR-/-mice compared to WT. Overall, our phenotype in adolescence is similar to models of William-Beuren syndrome that display sociability disinhibition and less anxiety (41). The increased social novelty behavior we observed in the adolescent SR-/-mice is similar to adolescent Grin1 hypomorph mice with near-complete loss of Grin1 expression (42).…”

“…There was an increase in connectivity in the default-mode network and a decrease in the salience network in the SR-/- mice compared to WT. Overall, our phenotype in adolescence is similar to models of William-Beuren syndrome that display sociability disinhibition and less anxiety ( 41 ).…”

The Impact of Mild Chronic Stress and Maternal Experience in the Fmr1 Mouse Model of Fragile X Syndrome

“…Recordings were then analyzed through Sonotrack Software (version 1.4.7, Metris B.V., Hoofddorp, The Netherlands) This software fully automatically recognizes several different USV types and also calculates quantitative parameters including the total number and mean duration of the calls. Based on previous literature on call types [22,[56][57][58][87][88][89], the following USV types were selected for automatic recognition in our dataset: short, flat, (ramp) up, (ramp) down, chevron, step-up, step-down, step-double (split), complex-3, complex-4, complex-5, complex-5+. Their characteristics are described in detail elsewhere [22,[56][57][58].…”

“…Based on previous literature on call types [22,[56][57][58][87][88][89], the following USV types were selected for automatic recognition in our dataset: short, flat, (ramp) up, (ramp) down, chevron, step-up, step-down, step-double (split), complex-3, complex-4, complex-5, complex-5+. Their characteristics are described in detail elsewhere [22,[56][57][58]. Definitions of call types were mutually exclusive.…”

“…Short gaps between components in both frequency (≤6 kHz) and time (≤5 ms) were interpolated (gaps can be caused by changes in microphone sensitivity or direction of vocalization). The calls classified as "complex-3 component" and "+3 component" were summed up into a "total complex" category, as in previous studies [22,[56][57][58].…”