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

Area of Science:

• Neuroscience
• Neurobiology
• Pharmacology

Background:

• Autism spectrum disorder (ASD) is characterized by social deficits and repetitive behaviors.
• Dysfunction in the GABAergic system is increasingly implicated in ASD pathophysiology.
• Endogenous allopregnanolone (ALLO), a GABA_A receptor modulator, plays a role in neurodevelopment.

Purpose of the Study:

• To investigate the role of endogenous ALLO in regulating ASD-like behaviors in male mice.
• To explore the effects of inhibiting ALLO biosynthesis on social behavior, repetitive actions, and learning.
• To determine if ALLO or methylphenidate (MPH) can reverse SKF-induced behavioral changes.

Main Methods:

• Male mice were treated with SKF105111 (SKF), a 5α-reductase inhibitor, to reduce brain ALLO levels.
• ASD-like behaviors were assessed using the 3-chamber test, open field social interaction, and resident-intruder tests.
• Olfactory function, anxiety, memory, and learning were evaluated using specific behavioral tests.
• The effects of ALLO and MPH administration on SKF-induced behaviors and brain ALLO levels were examined.
• Experiments were also conducted in female mice to assess sex differences.

Main Results:

• SKF treatment impaired sociability and induced repetitive grooming in male mice, without affecting olfactory function or anxiety.
• SKF did not alter short-term spatial working memory or long-term fear memory but enhanced latent learning.
• SKF-induced ASD-like behaviors and reduced brain ALLO levels were reversed by ALLO and MPH administration.
• SKF failed to induce ASD-like behaviors or alter brain ALLO levels in female mice, indicating sex-dependent effects.
• SKF's effects on brain ALLO levels were reversed by ALLO but not MPH.

Conclusions:

• Endogenous ALLO regulates ASD-like behaviors, likely through modulation of GABA_A receptors and their interaction with the dopaminergic system.
• A sex-dependent decrease in brain ALLO content may contribute to ASD pathophysiology, providing a potential animal model.
• Targeting the GABAergic system and ALLO levels could be a therapeutic strategy for specific features of ASD.