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Chronic corticosterone elevation suppresses adult hippocampal neurogenesis by hyperphorphorylating Huntingtin

on the July 10, 2020
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Chronic exposure to stress is a major risk factor for neuropsychiatric disease. Indeed, elevated plasma corticosterone (CORT; cortisol in human) correlates with reduced levels of both brain-derived neurotrophic factor (BDNF) and hippocampal neurogenesis, which predisposes to anxiety and depression.

To get further insight into how these phenomena are linked, the teams of S. Humbert and F. Saudou reconstituted the cortico-hippocampal neuronal network on a microfluidic chip and replicated the increased in CORT by treating the cells with the glucocorticoid receptor agonist dexamethasone.

Chronic dexamethasone treatment induces phosphorylation of the protein huntingtin -the protein whose mutation causes Huntington disease- by the cyclin dependent kinase 5 (CDK5) at serines 1181 and 1201. Phosphorylated huntingtin retards BDNF vesicular transport in cortical axons, thus reducing the supply of BDNF to the hippocampus.

Administration of CORT in drinking water of mouse induces anxiety and depression symptoms. In these mice, huntingtin is hyperphosphorylated, BDNF levels in the cortex and hippocampus are decreased and neurogenesis is drastically reduced in the hippocampus. The recently published work shows that the phosphorylation of huntingtin mediates the effects of CORT on neurogenesis and associated behaviors. Indeed, the deleterious effects of CORT on behaviour are attenuated in mutant mice whose 1181 and 1201 positions are not phosphorylatable and this protective effect of non-phosphorylatable huntingtin disappears if neurogenesis is suppressed.

This work describes huntingtin as a component of the pathways regulating stress-related mood disorders. Thus, the mood disturbances observed in Huntington's disease patients may result from changes in the normal function of huntingtin in this signaling pathway.

 

 
Reference:
Chronic corticosterone elevation suppresses adult hippocampal neurogenesis by hyperphorphorylating Huntingtin. F Agasse, I Mendez-David, W Christaller, R Carpentier, B Braz, DJ David, F Saudou and S Humbert. Cell Reports, in press.



Updated on July 13, 2020

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