Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model

Abstract

Williams Syndrome results in distinct behavioral phenotypes, which include learning deficits, anxiety, increased phobias and hypersociability. While the underlying mechanisms driving this subset of phenotypes is unknown, oxytocin (OT) dysregulation is hypothesized to be involved as some studies have shown elevated blood OT and altered OT receptor expression in patients. A "Complete Deletion" (CD) mouse, modeling the hemizygous deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These CD mice also exhibit impaired fear responses in the conditioned fear task. Here, we address whether OT dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an OT receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in CD mice. Thus, increased OT signaling is not acutely responsible for this phenotype. We also evaluated OT receptor and serotonin transporter availability in regions related to fear learning, memory and sociability using autoradiography in wild type and CD mice. While no differences withstood correction, we identified regions that may warrant further investigation.There was a nonsignificant decrease in OT receptor expression in the lateral septal nucleus and nonsignificant lowered serotonin transporter availability in the striatum and orbitofrontal cortex. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus.

Extensive characterization of a Williams Syndrome murine model showsGtf2ird1-mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior

“…This sex effect was also observed during contextual fear recall on Day 2 when mice were re-exposed to the spatial context to test hippocampal-dependent spatial conditioning ( Fig 3I ; F(1,85)=5.650, p=0.02). The CD mice also showed reduced freezing, similar to our previous reports ( Fig 3I,J ) (Nygaard et al . 2022), but did not pass the significance threshold.…”

“…This increased freezing was especially pronounced in females with the TG allele ( Fig 3K ; F(1,85)=11.876, p=0.0009). Mice with only the CD allele showed reduced freezing behavior compared to all other groups, replicating our previous effect (Nygaard et al . 2022), although the comparison to WT mice did not pass the significance threshold (p=0.078).…”

Activity-dependent translation dynamically alters the proteome of the perisynaptic astrocyte process

“…Two cohorts of mice were tested in a fear conditioning paradigm described previously ( Maloney et al, 2019 ; Nygaard et al, 2022 ). All animals were habituated to handling for multiple days prior to the start of testing.…”

Focus on autism and other neurodevelopmental disorders

“…The ultimate goal of animal models of neurodevelopmental disorders is to suggest treatments that could be tested in clinical trials. In this issue, Nygaard and colleagues investigated one such potential treatment in a mouse model of the Williams Syndrome (WS) 15 . WS results from a hemizygous deletion of 26–28 genes on Chromosome 7.…”

“…In this issue, Nygaard and colleagues investigated one such potential treatment in a mouse model of the Williams Syndrome (WS). 15 WS results from a hemizygous deletion of 26–28 genes on Chromosome 7. Symptoms of WS include craniofacial dysmorphology, connective and cardiac tissue abnormalities, complex cognitive, sensory processing disabilities, nonsocial anxiety, but surprisingly high sociability and emotional sensitivity to music.…”