OR01-05 Mechanisms of Increased Cognitive Flexibility in the Snord116del Mouse Model for Prader-Willi Syndrome

Abstract Disclosure: J.T. Reddaway: None. V. Plateau: None. S. Kocaturk: None. E. Guven: None. M. Assous: None. T. Humby: None. T. Wells: None. Prader-Willi syndrome (PWS) is a neurodevelopmental condition in which loss of gene expression from the PWS locus (15q11-q13) leads to profound metabolic and endocrine disturbances. Our understanding of the mechanisms underlying PWS-associated hyperphagia has advanced by studying mouse models for this condition, but the mechanisms giving rise to the cognitive changes of PWS remain unknown. To address this issue, we have studied the structure and function of cortical pyramidal neurons in mice bearing a deletion of the paternal copy of the PWS gene SNORD116. Loss of this non-coding RNA gene has previously been reported to disrupt cognitive behavior in mice. At 10 days of age (P10) Snord116del(p-/m+) mice showed a 7% reduction in cortical thickness (P=0.016) and Golgi-Cox-stained layer V/VI pyramidal neurons exhibited a 23% reduction in the branching of basal dendrites (P=0.030), while apical dendrites and spine density appeared relatively normal. This deficit became more pronounced with age with the emergence of structural changes in apical dendrite morphology, including the appearance of trifurcations. In addition, IBA1-positive cortical microglia displayed a more ramified/less reactive morphotype in Snord116del mice, suggesting a reduction in the pruning and remodeling of dendritic spines. Whole-cell patch clamp recordings showed that layer V pyramidal neurons from P60 Snord116del mice exhibited a marked elevation in spike discharge frequency in response to a depolarizing somatic current injection (P=0.037), a doubling of input resistance (P=0.004) and a 60% reduction in rheobase current (the minimum current required to elicit an action potential; P=0.015). Thus, these neurons exhibited a striking elevation in excitability. A visual discrimination task was used to establish the ability of Snord116del mice to adapt to a change in the association between a visual stimulus and a reward. While acquisition of the association was unchanged, Snord116del mice showed a progressive reduction in perseveration (the maintained response to a previously acquired association) on reversal of the stimulus. This effect became more pronounced after the second reversal, Snord116del mice showing a 50% reduction in perseveration (P<0.001), indicating a marked enhancement of cognitive flexibility. Although 4-month old Snord116del mice showed no change in anxiety-like behavior in an open field test, anxiety-like behavior was 33% higher in 1-year old Snord116del mice (P=0.015). Taken together, our data indicate that loss of the PWS gene, SNORD116, leads to reduced complexity in basal dendritic arborization of developing cortical pyramidal neurons and a striking elevation in excitability, potentially leading to the observed enhancement in cognitive flexibility. The relationship between these findings and the cognitive changes reported in human PWS is yet to be determined. Presentation: Saturday, July 12, 2025