Nicotine Attenuates Molecular Signalings in the BTBR T⁺ Itpr3^tf/J Mouse Model of Autism

Accumulating evidence indicates that nicotinic receptor subtypes are altered in the brains of autistic individuals, and nicotinic acetylcholine receptors (nAChRs) play essential roles in autistic profiles in BTBR T⁺ Itpr3^tf/J mice. This study aimed to elucidate the roles of nicotine on systemic inflammatory cytokine levels and expression patterns of nicotinic receptor subtypes in the prefrontal cortex in BTBR T⁺ Itpr3^tf/J mice. This research project characterized the effect of chronic treatment with nicotine at a dose (100 mcg/ml; po) administrated orally in drinking water over a period of fourteen days in BTBR T⁺ Itpr3^tf/J mice, while C57BL/6 J mice were served as the controls. Following the nicotine treatment, the levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ interleukin (IL)-1β, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assessed in the serum; the levels of pro-inflammatory cytokines [interleukin (IL)-17 and interferon (IFN)-γ], on CD4⁺ and CD8⁺ T cells were evaluated in the blood. Moreover, the expression of α7, α4, and β2-nAChRs in the prefrontal cortex in BTBR T⁺ Itpr3^tf/J mice was examined. Biochemical analysis showed that nicotine had significantly decreased the concentration of inflammatory cytokines, including TNF-α, IFN-γ, IL-1β, and GM-CSF in the serum, and reduced the expression levels of intracellular pro-inflammatory cytokines (IL-17 & IFN-γ) on CD4⁺ and CD8⁺ T cells in the blood while mecamylamine reversed the effect of IL-17⁺ CD4⁺ T cells. Nicotine administration up-regulated the expressions of α7, α4, and β2 nAChRs in the prefrontal cortex in BTBR T⁺ Itpr3^tf/J mice. The current results indicate that nAChRs play a significant role, at least in part, in ASD and might serve as a crucial target for therapeutic interventions in ASD.