Oxytocin ameliorates maternal separation‐induced ultrasonic vocalisation calls in mouse pups prenatally exposed to valproic acid

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder estimated by the World Health Organization to occur in one of 160 children worldwide. No pharmaceutical treatments are available to improve the deficits in social communication that are common symptoms of ASD. Recent clinical trials have focused on the nasal application of oxytocin, a neuronal peptide known to regulate a variety of social behaviours. However, the effect of oxytocin on this deficit is inconclusive. By contrast, evidence from ASD animal model studies indicates that when animals are treated with oxytocin during early development, improvements in social deficits are observed in adulthood. Thus, it is necessary to examine the effect of therapeutic target medication prescribed in early development. Mice prenatally exposed to valproic acid (VPA) are widely used as an animal model of ASD. However, many behavioural studies have been conducted during adulthood rather than early development. To establish a screening system to identify therapeutic drugs that are effective when delivered during the early postnatal period, it is important to examine the early developmental changes in their communicative behaviours. In the present study, we examined the ultrasonic vocalisation (USV) of VPA-exposed mice pups during their early postnatal developmental days. USV rates were comparable to those of the controls until the first week of their life but declined more on postnatal day 11. We checked the expression of oxytocin system in the hypothalamus and found the down-regulation of oxytocin and CD38, and up-regulation of oxytocin receptor in the VPA pups. Acute administration of oxytocin on postnatal day 11 increased the call rate of VPA pups.Taken together, we have demonstrated there was a deficiency in the oxytocinergic signalling in the VPA pups and also shown the existence of time periods that are effective with respect to screening the therapeutic drugs. K E Y W O R D Sautism spectrum disorder, early neurodevelopment, oxytocin, valproic acid mouse model

Maternal Diabetes-Induced Suppression of Oxytocin Receptor Contributes to Social Deficits in Offspring

“…We found that prenatal OXTR deficiency induces many social deficits in offspring, it mimics the effects of maternal diabetes-induced anxiety-like behavior and ultrasonic vocalization ( Tsuji et al, 2020 ), while has little effect on ALB. Very interestingly, prenatal OXTR deficiency potentiates maternal diabetes-mediated anxiety-like behavior while again having little effect on ALB, which is consistent with previous findings that OXT is associated with anxiety, but not necessarily with ALB ( Yoshida et al, 2009 ; Puglia et al, 2015 , 2018 ; Duque-Wilckens et al, 2020 ).…”

Excitatory and Inhibitory Synaptic Imbalance Caused by Brain-Derived Neurotrophic Factor Deficits During Development in a Valproic Acid Mouse Model of Autism

“…Valproic acid administration to pregnant rats and mice during gestation leads to autistic-like symptoms in the offspring, and this method is widely used as an animal model for autism ( Morales-Navas et al, 2020 ; Tsuji et al, 2020 ). USVs can be observed during the neonatal period, as these isolation-induced calls serve to elicit retrieval behavior from lactating mice ( Gzielo et al, 2020 ); thus, they may serve as communication signals between the mother and pups.…”

Rodent ultrasonic vocal interaction resolved with millimeter precision using hybrid beamforming

“…This is further supported by the modulatory effect that testosterone and oxytocin have on USV production. [39][40][41][42][43][44][45] Importantly, the neuronal circuitry underlying USVs has recently been identified and is being studied extensively. 20,25,[46][47][48][49][50][51][52][53] Because of their social and affective significance and our growing mechanistic understanding, mouse USVs are increasingly being used as a behavioral measure in neurodevelopmental and neurolinguistic translational research.…”