Drazan, T. M. | bioRxiv Science

bioRxiv2026

Preserved social development but impaired executive function in a Shank3-deficient rat model of Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by a microdeletion within chromosome 22q13.3 1-6, and accounts for [~]1-3% of cases of autism spectrum disorders (ASD). Individuals with PMS typically present with neonatal hypotonia, severe speech delay, intellectual disability, motor impairments, and autism-related features, although additional manifestations such as epilepsy, sleep disturbances, and developmental regression are common. As in ASD, there is considerable heterogeneity in cognitive and behavioral impairments in PMS, making it difficult to determine which features arise directly from SHANK3/Shank3 deficiency and how deficits manifest across development. In the present study, we transferred the targeted Shank3 mutation, previously characterized on the Sprague Dawley background, onto the Long-Evans strain and performed a longitudinal behavioral assessment of Shank3-deficient rats from infancy to adulthood. The rats were evaluated for delays in early sensory and motor development, and ultrasonic vocalizations as neonates, social behavior, short term memory and gait as juveniles, and cognitive-executive dysfunction using a touchscreen-based visual discrimination and reversal learning task as adults. Despite profound reductions and/or complete loss of Shank3 protein expression, heterozygous and homozygous male and female rats showed normal physical and neurological reflexes across development, yet female Shank3 knockout pups showed a selective reduction in distress-associated ultrasonic vocalizations. As juveniles, subtle abnormalities emerged in short-term memory and limb coordination, while social preference for novelty and recognition was normal. Prominent behavioral abnormalities were observed in adults characterized by rapid and error-prone responding to visual stimuli during discrimination learning and reversal. These data suggest that rats with complete or partial Shank3 deficiency produce a selective behavioral profile in which high-order cognitive dysfunction is more pronounced than deficits in basic sensorimotor or select social behaviors. More broadly, these findings highlight executive dysfunction as a key consequence of the loss of Shank3. For the first time, we report the loss of Shank3 expression on a Long-Evans background strain as a valuable translational tool for investigating cognitive dysfunction and therapeutic windows in Shank3-associated disorders.

animal behavior and cognition↗

bioRxiv2024

Improving reproductive success in captive marmosets through active female choice

The recent upsurge in the use of common marmosets (Callithrix jacchus) as a desirable model for high priority biomedical research has challenged local and global suppliers struggling to provide sufficient numbers of marmosets for large scale projects. Scientific research laboratories are increasingly establishing institutional breeding colonies, in part to combat the resulting shortage and high cost of commercially available animals, and in part to have maximum control over research lines involving reproduction and development. For such laboratories, efficient marmoset breeding can be challenging and time consuming. Random male/female pairings are often unsuccessful, with intervals of several months before attempting alternate pairings. Here we address this challenge through a behavioral task that promotes self-directed female selection of potential mates to increase the efficiency of breeding in captive marmosets. We created a partner preference test ( love maze) in which nulliparous females (n=12) had the opportunity to select between two eligible males (n=23) at a time, in a forced choice test. In this test, both males usually displayed sexual solicitations. However, the female would clearly indicate her preference for one. Most commonly, the female actively ignored the non-preferred male and directed overt prosocial behaviors (e.g. proceptive tongue-flicking, approach and grooming) to the preferred male. Moreover, once a male was selected in this context, the female would continue to prefer him over other males in three consecutive testing sessions. Compared with random pairings, this directed female choice showed a 2.5-fold improvement in breeding within 90 days compared to random pairings. This cost-effective and straightforward pairing practice can be used to enhance breeding efficiency in both small and large marmoset colonies.

animal behavior and cognition↗