Repeated Exposure to Sevoflurane in Neonatal Mice Induces Cognitive and Synaptic Impairments in a TTLL6-Mediated Tubulin Polyglutamylation Manner.

AIMS: Repeated sevoflurane exposure during the neonatal stage may induce Tau phosphorylation, dendritic spine loss, and neurocognitive impairment in the developing brain. Tubulin tyrosine ligase like-6 (TTLL6), which aggregates in dendrites due to Tau missorting, regulates microtubule stability via α-tubulin polyglutamylation. Meanwhile, Spastin modulates dendritic spine formation by severing microtubules. We hypothesize that repeated sevoflurane treatment impairs dendritic spine remodeling in neonatal mice by enhancing TTLL6-mediated tubulin polyglutamylation and increasing Spastin expression, leading to cognitive dysfunction in their pre-adolescent stage. METHODS: Six-day-old wild type (WT), TTLL6 brain conditional knockout (TTLL6(CKO)), TTLL6-flox (TTLL6(CON)) and Tau-knockout mice were treated with 3% sevoflurane for 2 h daily on postnatal days (P) 6, 8, and 10. Levels of Tau, phosphorylated Tau (pTau), TTLL6, polyglutamylated tubulin, ATP, Spastin, PSD95, Tau-TTLL6 interaction, Tau-TTLL6 missorting, dendritic spine remodeling, and behavioral alterations were compared across these groups. RESULTS: Repeated sevoflurane exposure during brain development in neonatal mice could reduce dendritic spine density, synapse number, PSD95, and ATP levels, while increasing pTau, polyglutamylated tubulin, Tau-TTLL6 missorting from axons to the somatodendritic compartment, and Spastin levels, leading to cognitive impairment later in their pre-adolescent stage (P30). However, these changes were ameliorated in the TTLL6(CKO) mice. CONCLUSIONS: Repeated neonatal sevoflurane exposure results in synaptic impairment through TTLL6-mediated tubulin polyglutamylation and increased Spastin expression, causing pre-adolescent cognitive dysfunction in mice. This process is initiated by Tau phosphorylation and missorting from axons to somatodendritic compartments.