Exposure to GABAA Receptor Antagonist Picrotoxin in Pregnant Mice Causes Autism-Like Behaviors and Aberrant Gene Expression in Offspring

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by impairments in social interaction and restricted/repetitive behaviors. The neurotransmitter γ-aminobutyric acid (GABA) through GABAA receptor signaling in the immature brain plays a key role in the development of neuronal circuits. Excitatory/inhibitory imbalance in the mature brain has been investigated as a pathophysiological mechanism of ASD. However, whether and how disturbances of GABA signaling in embryos that are caused by GABAA receptor inhibitors cause ASD-like pathophysiology are poorly understood. The present study examined whether exposure to the GABAA receptor antagonist picrotoxin causes ASD-like pathophysiology in offspring by conducting behavioral tests from the juvenile period to adulthood and performing gene expression analyses in mature mouse brains. Here, we found that male mice that were prenatally exposed to picrotoxin exhibited a reduction of active interaction time in the social interaction test in both adolescence and adulthood. The gene expression analyses showed that picrotoxin-exposed male mice exhibited a significant increase in the gene expression of odorant receptors. Weighted gene co-expression network analysis showed a strong correlation between social interaction and enrichment of the “odorant binding” pathway gene module. Our findings suggest that exposure to a GABAA receptor inhibitor during the embryonic period induces ASD-like behavior, and impairments in odorant function may contribute to social deficits in offspring.

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

“…These changes have been associated with impairments in fear conditioning, object recognition ( 94 ), and ASD-like social deficits ( 94 , 95 ). Interestingly, the prenatal inhibition of GABAergic signaling with GABA receptor antagonists, such as picrotoxin administration on E10-12, suppressed neurogenesis in the fetal brain ( 97 ) and resulted in ASD-like social deficits in offspring ( 97 , 98 ). These findings suggest that GABA signaling should be controlled within a limited range to maintain normal development of the fetal brain.…”

Association of early childhood constipation with the risk of autism spectrum disorder in Taiwan: Real-world evidence from a nationwide population-based cohort study

“…The enrolled children were followed up until the diagnosis of autism, 31 December 2013, or withdrawal from the national health insurance system, whichever happened prior to constipation. In order to ensure that every autistic condition developed after constipation, we excluded the following children: ( 1 ) pediatric patients with missing demographics, ( 2 ) born before 2001, ( 3 ) children diagnosed with autism before the index date, ( 4 ) those whose diagnoses were made after 2011.…”

“…These factors and the resultant variety of symptoms mean that the therapeutic targets are complex. Efforts are underway to find genetic or pathophysiological pathways shared by animal models and humans in order to identify a common method for better treatment targeting (4). The roles of prenatal exposure to risk factors, such as maternal-specific drug use, prenatal steroid exposure, old parental age, and use of antibiotics in the prevention of autism have been investigated in recent years (5)(6)(7).…”

Correlations between stereotypies in ASD and neurotransmitters: a systematic review

“…Likewise, the inhibition of the GABAA receptor, through the administration of the antagonist picrotoxin, demonstrated an increase in self-grooming 57 . These results are consistent with the idea that stereotypes may be associated with increased excitatory activity in the CNS.…”