The GABAB receptor agonist STX209 reverses the autism‑like behaviour in an animal model of autism induced by prenatal exposure to valproic acid

Abstract

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition characterized by impaired social interaction, compromised communication, and restrictive or stereotyped behaviours and interests. Due to the complex pathophysiology of ASD, there are currently no available medical therapies for improving the associated social deficits. Consequently, the present study investigated the effects of STX209, a selective γ-aminobutyric acid type B receptor (GABABR2) agonist, on an environmental rodent model of autism. The mouse model of autism induced by prenatal exposure to valproic acid (VPA) was used to assess the therapeutic potential of STX209 on autism-like behaviour in the present study. This study investigated the effects of STX209 on VPA model mice via behavioral testing and revealed a significant reversal of core/associated autism-like behavior, including sociability and preference for social novelty, novelty recognition, locomotion and exploration activity and marble-burying deficit. This may be associated with STX209 correcting dendritic arborization, spine density and GABABR2 expression in hippocampus of VPA model mice. However, expression of glutamic acid decarboxylase 65/67 in the hippocampus were not altered by STX209. The present results demonstrated that STX209 administration ameliorated autism-like symptoms in mice exposed to VPA prenatally, suggesting that autism-like symptoms in children with a history of prenatal VPA exposure may also benefit from treatment with the GABABR2 agonist STX209.

Ethanolamine and vinyl-ether moieties in brain phospholipids modulate behavior in rats

“…Thus, elevated PE in the frontoparietal region may reduce exploratory behavior. In accord with this nding, a valproic acid-induced autistic mouse model with elevated PE in the cortex, hippocampus, thalamus, hypothalamus, cerebellum, and brain stem [29] also spent less time in the central region of the OF [30] as well as reduced exploratory activity [31] compared to control mice.…”

Correlations between stereotypies in ASD and neurotransmitters: a systematic review

“…Table 3 summarizes the findings of each article. 16 Yes Yes Yes NR NR Yes NA NA Yes Yes Yes Yes Yes Yes Canal 2015 17 Yes Yes Yes Yes Yes Yes NA NA Yes Yes Yes Yes Yes Yes Mohammadi 2019 18 Yes Yes Yes Yes Yes Yes NA NA Yes Yes Yes Yes Yes Yes Jiang 2022 19 Yes Yes Yes NR NR Yes NA NA Yes Yes Yes Yes Yes Yes Jiang 2022 20 Yes Yes Yes Yes Yes Yes NA NA Yes Yes Yes Yes Yes Yes Silverman 2015 21 Yes Yes Yes Yes Yes Yes NA NA Yes Yes Yes Yes Yes Yes Venkatachalam 2021 22 Yes Yes Yes NR NR Yes NA NA Yes Yes Yes Yes Yes Yes Yang 2021 23 Yes Yes Yes NR NR Yes NA NA Yes Yes Yes Yes Yes Yes Yang 2021 24 Yes Yes Yes NR NR Yes NA NA Yes Yes Yes Yes Yes Yes Yoshimura 2017 25 Yes Yes Yes Yes Yes Yes NA NA Yes Yes Yes Yes Yes Yes…”

“…Muscarinic acetylcholine receptors (mAChRs), coupled to the G protein, have excitatory and inhibitory functions in the central nervous system, being part of postsynaptic excitation and pre and postsynaptic inhibition, even possessing mechanisms of self-inhibition 78 . There is evidence that these receptors can also modulate dopaminergic activity in some brain areas, such as the dorsal striatum, which has been associated with the development of stereotypes 19,79 . O Oxytremonine (mAChR agonist) causes decreased selfgrooming behavior in BTBR mice 80 .…”

“…stereotypes, similar to what was seen with GABAA receptors, Silverman 201521 showed that intraperitoneal administration of selective GABAB receptor agonist Rbaclofen and Baclofen strongly reduced stereotypic and repetitive behaviors in two mouse strains (BTBR and C58), such as self-grooming, high marble burying, and high vertical jumping. In addition to reducing stereotypies, this GABAergic agonist was shown to be able to reduce anxiety behaviors, therefore improving sociability deficits in mice exposed to valproic acid (VPA), as demonstrated by Jiang 202219 and Jiang 202220 .Thus, the pathophysiology of stereotypies may have a common path with the pathophysiology of the social behavior of the individual with autism, so that future treatments based on this neurotransmitter could improve all the central symptoms of ASD. Thus, new experimental studies focused on GABA agonism may demonstrate a great improvement in the issue of sociability and motor behavior of these individuals.Confirming the results, a study that evaluated GABAA and GABAB receptor agonists demonstrated that the activation of these receptors can reverse the typical behaviors of autism in mice exposed to VPA.…”

Pre-autism: What a paediatrician should know about early diagnosis of autism‎

“…This imbalance was proved by genetic analysis of the expression of the functional genes responsible for the inhibitory function and post-mortem and animal studies that demonstrated the reduction of the inhibitory neurons[ 33 ]. Treating this imbalance using medications that boost GABAergic signaling, such as certain antiepileptics, benzodiazepines, and GABAB receptor agonist STX209, has been proven effective in treating some autism symptoms, with variable degrees of success[ 34 ].…”