E159, A HISTAMINE H3 RECEPTOR ANTAGONIST, AMELIORATES ASD-RELATED BEHAVIOURS BY ENHANCING AUTOPHAGY AND HIPPOCAMPAL NEUROGENESIS IN BTBR MICE

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social interaction, repetitive behaviors, and dysregulated neuroimmune homeostasis. Emerging evidence suggests that disrupted autophagy and reduced hippocampal neurogenesis also contribute to the pathophysiology of ASD. Histamine H3 receptor (H3R) antagonists have emerged as promising therapeutic candidates due to their modulatory effects on neurotransmission, inflammation and cognitive function. The study evaluated the effects of sub-chronic administration of the selective H3R antagonist E159 on behavioral, neuroinflammatory, autophagic and neurogenic characteristics in male BTBR T+tf/J mice, an idiopathic model of ASD. We also investigated whether co-treatment with the CNS-penetrant H3R agonist (R)-α-methylhistamine (MHA) could reverse E159-mediated behavioral and biochemical improvements, thereby elucidating the role of brain histaminergic neurotransmission. E159 (2.5 mg/kg, i.p.) significantly improved ASD-like phenotypes as evidenced by reduced stereotypic marble-burying behavior, enhanced learning and cognitive flexibility in the Barnes maze and fear conditioning tests and increased social preference in the three-chamber test. E159 also attenuated neuroinflammation, by decreasing pro-inflammatory cytokine expression in the cerebellum and hippocampus. In addition, E159 elevated cerebral and hippocampal expression of autophagy-related proteins LC3A/B and Beclin-1, indicating the restoration of impaired autophagy. Furthermore, E159 enhanced hippocampal neurogenesis, demonstrated by increased number of DCX⁺ immature neurons in the dentate gyrus. Notably, co-administration with the CNS-penetrant and selective H3R agonist MHA reversed these beneficial effects, confirming the involvement of histaminergic neurotransmission. These findings suggest that H3R antagonism with E159 improves ASD-like behaviors, by promoting autophagy and neurogenic processes while attenuating neuroinflammation, supporting its therapeutic potential for ASD.