Decrease in endogenous brain allopregnanolone induces autism spectrum disorder (ASD)-like behavior in mice: A novel animal model of ASD.

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABAA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABAA receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD.

• Authors: Ken Ebihara, Hironori Fujiwara, Suresh Awale, Dya Fita Dibwe, Ryota Araki, Takeshi Yabe, Kinzo Matsumoto
• Journal: Behavioural brain research (Behav Brain Res) Vol. 334 Pg. 6-15 (09 15 2017) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 28743598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• 5-alpha Reductase Inhibitors
• Androstanes
• Psychotropic Drugs
• SKF 105111
• Methylphenidate
• Pregnanolone

Topics

• 5-alpha Reductase Inhibitors (pharmacology)
• Androstanes
• Animals
• Anxiety (metabolism)
• Autism Spectrum Disorder (drug therapy, metabolism, psychology)
• Brain (drug effects, metabolism)
• Disease Models, Animal
• Fear (physiology)
• Female
• Grooming (physiology)
• Learning (physiology)
• Male
• Memory (physiology)
• Methylphenidate (pharmacology)
• Mice, Inbred ICR
• Pregnanolone (deficiency)
• Psychotropic Drugs (pharmacology)
• Sex Characteristics
• Social Behavior
• Stereotyped Behavior (physiology)