Behavioral impairment associated with dysfunction of myelination by Shati/Nat8L deficit in mice

Abstract

[Background] We found Shati/Nat8l increase in the mice brain of mice treated with methamphetamine. SHATI is N-acetyltransferase 8-like protein (NAT8L) that produces N-acetylaspatate (NAA) from aspartate and acetyl-CoA in the neuron. We produced Shati/Nat8l knockout (Shati-/-) mouse that demonstrated behavioral deficits, such as hyperactivity and social interaction, that were not rescued by single NAA supplementation. This reason is still not clarified. It is possible that the developmental impairment results from deletion of Shati/Nat8l in the mouse brain, because NAA is involved in myelination through lipid synthesis in the oligodendrocytes. However, it remains unclear whether Shati/Nat8l is involved in brain development.

[Methods] We investigated mRNA level of Shati/Nat8l in developmental stage by using real-time RT-PCR. We also evaluated the difference in myelin basic protein (MBP) level of Shati-/- and wild type (Shati+/+) mice by immunohistochemistry and Western blotting. Next, we conducted administration of glyceryltriacetate (GTA), which metabolized to acetate and distributed to the brain rapidly after oral administration, to Shati-/- and Shati+/+mice from juvenile, followed by performing locomotor activity, three chamber social interaction test and elevated-plus maze test. Furthermore, we observed G-ratio to confirm whether GTA treatment influences on myelination in the brain of Shati-/- and Shati+/+mice by using electron microscopy.

[Results] We found that the expression of Shati/Nat8l mRNA was increased with brain development in mice, and that there was a reduction in the MBP level in the prefrontal cortex of juvenile, but not adult, Shati-/- mice. Next, We found that deletion of Shati/Nat8l induces several behavioral deficits in mice, and that GTA treatment ameliorates the behavioral impairments and normalizes the reduced protein level of MBP in juvenile Shati-/- mice.

[Conclusions] These findings suggest that Shati/Nat8l is involved in myelination in the juvenile mouse brain via supplementation of acetate derived from NAA. Thus, reduction of Shati/Nat8l induces developmental disorders.