Tet1-mediated 5-hydroxymethylcytosine alterations in the olfactory bulb are associated with aberrant neurogenesis and PI3K-Akt signaling in response to CIH.
TL;DR
Tet1 knockdown in the OB partially normalized PI3K-Akt signaling, was associated with improved neurogenesis markers, and alleviated CIH-induced olfactory dysfunction, suggesting that Tet1 may serve as a potential therapeutic target for CIH-related sensory impairment.
Abstract
Chronic intermittent hypoxia (CIH), a key feature of obstructive sleep apnea, impairs central nervous system function, but its effects on olfactory bulb (OB) and epigenetic mechanisms are unclear. We show that CIH causes olfactory behavioral deficits in mice with structural and molecular OB changes. CIH disrupted adult OB neurogenesis, increasing the immature neuron marker doublecortin (DCX) and reducing mature NeuN expression, and activated microglia. At the molecular level, CIH markedly upregulated the DNA demethylation enzyme Tet1 and global 5-hydroxymethylcytosine (5hmC) levels, which were accompanied by aberrant activation of the PI3K-Akt pathway. Importantly, Tet1 knockdown in the OB partially normalized PI3K-Akt signaling, was associated with improved neurogenesis markers, and alleviated CIH-induced olfactory dysfunction. These results suggest that Tet1-dependent epigenetic remodeling represents an important molecular mechanism linking CIH to OB dysfunction, and that Tet1 may serve as a potential therapeutic target for CIH-related sensory impairment.