Abstract：
: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 (HdhS1181A/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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Agasse F,Mendez-David I,Christaller W,Carpentier R,Braz BY,David DJ,Saudou F,Humbert Sdoi
10.1016/j.celrep.2020.107865subject
Has Abstractpub_date
2020-07-07 00:00:00pages
107865issue
1issn
2211-1247pii
S2211-1247(20)30846-9journal_volume
32pub_type
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