Vulnerability to depressive behavior induced by overexpression of striatal Shati/Nat8l via the serotonergic neuronal pathway in mice

Abstract

The number of patients with depressive disorders is increasing. However, the mechanism of depression onsets has not been completely revealed. We previously identified Shati/Nat8l, an N-acetyltransferase, in the brain using an animal model of psychosis. In this study, we revealed the involvement of Shati/Nat8l in the vulnerability to major depression. Shati/Nat8l mRNA was increased only in the striatum of mice, which were exposed to chronic social defeat stress. Shati/Nat8l-overexpressed mice showed impairment in social interaction and sucrose preference after the subthreshold social defeat (microdefeat) stress. These depressionlike behaviors were restored by fluvoxamine and LY341495 injection prior to these tests. Furthermore, the intracerebral administration of only fluvoxamine, but not of LY341495, to the dorsal striatum and direct infusion of LY341495 to the dorsal raphe also rescued. Taken together, Shati/Nat8l in the striatum has an important role in the vulnerability to depression onsets by regulating the origin of serotonergic neuronal system via GABAergic projection neuron in the dorsal raphe from the dorsal striatum.

Investigating DNA Methylation of <i>SHATI/NAT8L</i> Promoter Sites in Blood of Unmedicated Patients with Major Depressive Disorder

“…However, some studies have reported that epigenetic regulation in the brain and peripheral blood may have anti-parallel relationship. 24,25) In fact, Shati/Nat8l mRNA is increased in the striatum in a mouse model of depression. 26) Two possibilities are considered in this deference relationship of expression between in blood and brain: The first possibility is that altered expression of SHATI/NAT8L is region-or tissue-specific.…”

A Role of BDNF in the Depression Pathogenesis and a Potential Target as Antidepressant: The Modulator of Stress Sensitivity “Shati/Nat8l-BDNF System” in the Dorsal Striatum

“…Miyamoto et al demonstrated increased Shati/Nat8l in the dorsal striatum following repeated forced-swimming stress [ 135 ]. Uno et al also demonstrated upregulated striatal Shati/Nat8l expression by RSDS [ 152 ]. The expression of Shati/Nat8l in regions other than the dorsal striatum was not altered in these studies.…”

“…The ratio of stress-susceptible mice after RSDS increased three-fold with Shati/Nat8l overexpression compared with control mock mice. Furthermore, these mice also showed susceptibility to microdefeat stress [ 152 ]. Decreased serotonin levels were observed in the brains of STR-Shati OE mice [ 135 ].…”

“…Decreased serotonin levels were observed in the brains of STR-Shati OE mice [ 135 ]. The impairment of stress sensitivity in these mice was recovered by treatment with the selective serotonin reuptake inhibitor (SSRI), fluvoxamine [ 152 ], suggesting that the serotonergic system is downstream of the Shati/Nat8l pathway in depression pathogenesis. In contrast, resilience to RSDS was established by conditional knockdown of Shati/Nat8l in the dorsal striatum.…”

“…These considerations are consistent with our report that dorsal striatal overexpression of Shati/Nat8l induced vulnerability to stress accompanied by a decline in serotonin [ 135 ]. The impairment of sensitivity to stress by the overexpression of Shati/Nat8l in the dorsal striatum was attenuated by activation of DRN or systemic administration of SSRI [ 152 ]. These findings suggested that Shati/Nat8l overexpression in the dorsal striatum inactivates serotonergic systems from the DRN, thereby suppressing serotonin release.…”