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

Abstract

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 memory) as well as time-variant conditions (episodic-like memory) implicating a robust nootropic effect. This was the first proof-of-concept study of HU treatment in a DS model, and indicates that further studies are warranted to assess a window to optimize timing and dosage of the treatment in this pre-clinical phase. Findings of this study indicate that HU has potential for improving memory retention and cognitive flexibility that can be harnessed for the amelioration of cognitive deficits in normal aging and in cognitive decline (dementia) related to DS and other neurodegenerative diseases.

A non-mosaic transchromosomic mouse model of Down syndrome carrying the long arm of human chromosome 21

“…The forgetting of non-essential memory is an important component of learning and can be assessed by reversal water maze ( Nonaka et al, 2017 ; Brose et al, 2019 ), and previous study showed that female but not male APP/PS1 mice showed deficits in this paradigm ( Gallagher et al, 2013 ). Immediately following the 72 h probe trials of MWM, females (Eu (n=10), TcMAC21 (n=9)) were tested in RRWM that had the same spatial reference as MWM and consisted of two reversal sessions.…”

Hydroxyurea affects in vitro porcine oocyte maturation through increased apoptosis and oxidative stress

“…Hydroxyurea (HU), a United States Food and Drug Administration-approved drug [1], is an inhibitor of ribonucleotide reductase commonly used to treat myeloproliferative disorders and sickle cell anemia [2]. In addition, HU is used as an anti-tumor drug to treat various malignancies [3].…”

Forebrain Shh overexpression improves cognitive function and locomotor hyperactivity in an aneuploid mouse model of Down syndrome and its euploid littermates

“…People with DS have a high risk of developing early-onset dementia, and previous studies show that Ts65Dn mice lose the ability to acquire any spatial learning and memory in MWM at ~ 6-month-old [ 11 , 12 ]. To analyze the effects of forebrain hShh overexpression on early-onset severe cognitive impairment in Ts65Dn, we tested the forebrain-cohort in an MWM decorated with different spatial references at 7-month-old.…”