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September 16, 2025Open Access

Simultaneous G9a inhibition and histamine H3 receptor antagonism modulate autism-like behaviours and neuroinflammation in BTBR T+tf/J Mice

MHMalak HajarUnited Arab Emirates University HSHolger StarkGoethe University Frankfurt BSBassem SadekGoethe University Frankfurt

Key Points

A-366 significantly reduced anxiety and repetitive behaviors in BTBR T+tf/J mice.
Chronic treatment led to decreased neuroinflammation markers in mouse cerebellar and hippocampal tissues.
The study utilized a variety of behavioral tests to evaluate the impact of G9a inhibition and H3 receptor antagonism.
Findings indicate that dual-targeting of G9a and H3Rs could be a valuable therapeutic strategy for autism spectrum disorder.

Abstract

Introduction Autism Spectrum Disorder (ASD) is a complex neuropsychiatric disorder characterized by deficits in social interaction, anxiety and the presence of repetitive-ritualistic behaviours. Recent studies suggest that epigenetic mechanisms, such as histone methylation, play a crucial role in the etiology of ASD by regulating gene expression linked to neuronal differentiation and proliferation. The enzyme, G9a is responsible for histone H3K9 methylation, and its inhibition has shown promise in altering epigenetic pathways associated with ASD onset and progression. Similarly, histamine H3 receptor (H3R) has long been recognized as a potential therapeutic target for ASD treatment Objectives This study aimed to investigate the dual action of A-366, a potent G9a inhibitor with high and selective H3R antagonistic affinity, on the ASD-like behaviours and neuroinflammation of male BTBR T+tf/J mice model. Methods Male BTBR T+tf/J mice were housed under standard conditions and treated chronically with A-366 (0.5-2 mg/kg, i.p.) for 21 days. ASD-like behaviors were assessed using the Marble Burying Test, Nestlet Shredding Test, Self-Grooming Test, Spontaneous Alteration Test, Elevated Plus Maze, Light Dark Box, and Three-Chamber Test. Following behavioral testing, cerebellar and hippocampal brain tissues were analyzed using ELISA to quantify pro-inflammatory markers (TNF-α, TNF-β, IL-6, IL-1β, TGF-β) and immunohistochemistry for Iba-1 expression to evaluate neuroinflammation. Results A dose dependent decrease of repetitive and anxiety-like behaviours as well as amelioration in social deficits was observed in response to the chronic systemic treatment of A-366 (0.5-2 mg/kg, i.p.). Moreover, A-366 decreased neuroinflammation in cerebellar and hippocampal brain tissues of treated BTBR mice, as evidenced by the reduction in proinflammatory markers TNF-α, TNF-β, IL-6, IL-1β and TGF-β, as well as the decrease in Iba-1 expression. Conclusions This in vivo study demonstrates the potential therapeutic value of A-366 as a dual-targeting agent for G9a and H3Rs, with modulatory role on epigenetic, neuroinflammation, and brain histaminergic neurotransmission. Therefore, A-366 is expected to provide a lead template for future design and synthesis of a novel, potent and selective class of drugs to target ASD features. Disclosure of Interest None Declared

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