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.