Chronic Corticosterone Elevation Suppresses Adult Hippocampal Neurogenesis by Hyperphosphorylating Huntingtin

被引：32

作者：

Agasse, Fabienne ^{[1
]}

Mendez-David, Indira ^{[2
]}

Christaller, Wilhelm ^{[1
]}

Carpentier, Remi ^{[1
]}

Braz, Barbara Y. ^{[1
]}

David, Denis J. ^{[2
]}

Saudou, Frederic ^{[1
]}

Humbert, Sandrine ^{[1
]}

机构：

[1] Univ Grenoble Alpes, Grenoble Inst Neurosci, CHU Grenoble Alpes, U1216,INSERM, F-38000 Grenoble, France

[2] Univ Paris Saclay, Fac Pharm, Ctr Rech Epidemiol & Sante Populat CESP, INSERM, F-92290 Chatenay Malabry, France

来源：

CELL REPORTS | 2020年 / 32卷 / 01期

关键词：

VENTRAL TEGMENTAL AREA; STRESS; BDNF; NEURONS; MODEL; CDK5; TRANSPORT; RECEPTOR; DIFFERENTIATION; COMPARTMENT;

D O I：

10.1016/j.celrep.2020.107865

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Chronic exposure to stress is a major risk factor for neuropsychiatric disease, and elevated plasma corticosterone (CORT) correlates with reduced levels of both brain-derived neurotrophic factor (BDNF) and hippocampal neurogenesis. Precisely how these phenomena are linked, however, remains unclear. Using a cortico-hippocampal network-on-a-chip, we find that the glucocorticoid receptor agonist dexamethasone (DXM) stimulates the cyclin-dependent kinase 5 (CDK5) to phosphorylate huntingtin (HTT) at serines 1181 and 1201 (S1181/1201), which retards BDNF vesicular transport in cortical axons. Parallel studies in mice show that CORT induces phosphorylation of these same residues, reduces BDNF levels, and suppresses neurogenesis. The adverse effects of CORT are reduced in mice bearing an unphosphorylatable mutant HTT (Hdh(S1181A/S1201A)). The protective effect of unphosphorylatable HTT, however, disappears if neurogenesis is blocked. The CDK5-HTT pathway, which regulates BDNF transport in the cortico-hippocampal network, thus provides a missing link between elevated CORT levels and suppressed neurogenesis.

引用

页数：15

共 56 条

[1] Acute or chronic stress induce cell compartment-specific phosphorylation of glucocorticoid receptor and alter its transcriptional activity in Wistar rat brain [J].