Hydroxyurea Improves Spatial Memory and Cognitive Plasticity in Mice and Has a Mild Effect on These Parameters in a Down Syndrome Mouse Model

作者：Rebecca Deering Brose, Alena Savonenko, Benjamin Devenney, Kirby D. Smith, Roger H. Reeves · 发表于：Frontiers in Aging Neuroscience · 年份：2019 · DOI：10.3389/fnagi.2019.00096 · 被引用次数：15 · 研究领域：Down syndrome and intellectual disability research、Genetics and Neurodevelopmental Disorders、Cardiovascular Function and Risk Factors

Down syndrome (DS), a genetic disorder caused by partial or complete triplication of chromosome 21, is the most common genetic cause of intellectual disability. DS mouse models and cell lines display defects in cellular adaptive stress responses including autophagy, unfolded protein response, and mitochondrial bioenergetics. We tested the ability of hydroxyurea (HU), an FDA-approved pharmacological agent that activates adaptive cellular stress response pathways, to improve the cognitive function of Ts65Dn mice. The chronic HU treatment started at a stage when early mild cognitive deficits are present in this model (∼3 months of age) and continued until a stage of advanced cognitive deficits in untreated mice (∼5-6 months of age). The HU effects on cognitive performance were analyzed using a battery of water maze tasks designed to detect changes in different types of memory with sensitivity wide enough to detect deficits as well as improvements in spatial memory. The most common characteristic of cognitive deficits observed in trisomic mice at 5-6 months of age was their inability to rapidly acquire new information for long-term storage, a feature akin to episodic-like memory. On the background of severe cognitive impairments in untreated trisomic mice, HU-treatment produced mild but significant benefits in Ts65Dn by improving memory acquisition and short-term retention of spatial information. In control mice, HU treatment facilitated memory retention in constant (reference me...