Histamine and H1R regulate microglia in an IDPN-Induced Mouse Model of Tic-like behaviors

Tic disorder (TD) is a developmental neurological condition characterized by pathological motor and/or vocal tics. Accumulating evidence suggests that central histamine (HA) participates in the onset and development of TD. Recent research highlights HA’s role in neuroinflammation, and microglia the central resident phagocytes are closely associated with HA in neuroinflammatory conditions. Clinical studies have associated H1 receptor (H1R) antagonist exposure with increased TD risk and symptom severity; however, causal evidence remains limited, and the precise pathogenesis is unclear. This study investigated the HA-H1R pathway and microglial reactivity in a β,β′-iminodipropionitrile (IDPN)-induced mouse model of tic-like behaviors. IDPN‑treated mice showed reduced HA and H1R expression in the hypothalamus. Intraperitoneal administration of the brain-penetrant H1R antagonist diphenhydramine (DPH) induced tic-like stereotyped behaviors in wild-type mice. IDPN-treated mice also showed increased striatal Iba-1 immunoreactivity. Intrastriatal HA injection reduced stereotyped behavior and Iba-1 immunoreactivity in IDPN-treated mice, and these effects were attenuated by DPH pretreatment. These findings support an association between altered HA-H1R signaling and tic-like behaviors in this model and suggest that microglial reactivity may be involved. The results should be interpreted as hypothesis-generating because the study used a pharmacological antagonist approach and did not include genetic H1R manipulation or direct microglia-specific intervention.