Superior working memory and behavioural habituation but diminished psychomotor coordination in mice lacking the ecto-5′-nucleotidase (CD73) gene

Abstract

Adenosine is an important neuromodulator in the central nervous system involved in the regulation of wakefulness, sleep, learning and memory, fear and anxiety as well as motor functions. Extracellular adenosine is synthesized by the cell-surface ectoenzyme ecto-5′-nucleotidase (CD73) from 5′-adenosine monophosphate. While CD73 is widely expressed throughout the mammalian brain, its specific role for behaviour is poorly understood. We examined spatial working memory, emotional responses, motor coordination and motor learning as well as behavioural habituation in mice with a targeted deletion of CD73. CD73 knockout (CD73−/−) mice exhibit enhanced spatial working memory in the Y-maze and enhanced long-term behavioural habituation in the open field. Furthermore, impaired psychomotor coordination on the accelerating rotarod was found in CD73−/− mice. No changes in motor learning and/ or anxiety-like behaviour were evident in CD73−/− mice.Our data provide evidence for a role of CD73 in the regulation of learning and memory and psychomotor coordination. Our results might be important for the evaluation of adenosine neuromodulators as possible treatments to ameliorate cognitive and motor deficits associated with neurodegenerative diseases.

Sleep-Wake Regulation and Its Impact on Working Memory Performance: The Role of Adenosine

“…In line with this result, WM performance was reduced in rats overexpressing A 2A receptors in the cortex, hippocampus and cerebellum [ 167 ]. Knock-out of a gene encoding ecto-5′-nucleotidase, an enzyme converting adenosine monophosphate into adenosine, was associated with increased WM performance [ 166 , 168 ]. Furthermore, A 2A receptor knock-out in the entire brain [ 169 ], and in particular in the striatum [ 170 ], has been linked to enhancements in WM performance.…”

Purinergic system dysfunction in mood disorders: a key target for developing improved therapeutics

“…Enzymes of this cascade function in mood and somatic symptoms. e5NT knockout mice lack non-REM sleep responses to sleep deprivation, but no changes in anxiety-like behaviors were evident in these knock-out mice (Zlomuzica et al, 2013). Lithium, used to treat BD, inhibits ectonucleotidase activity (Oliveira Rda et al, 2011).…”

5'-Nucleotidases, Nucleosides and their Distribution in the Brain: Pathological and Therapeutic Implications

“…Thus, increased activity of e5'NT after brain injury, epilepsy and other conditions may be an adaptive response that increases the levels of extracellular Ado and enhances its neuroprotective/anti-epileptic/anti-epileptogenetic effects via A 1 receptors [1,13,79,349]. In addition, modulation of e5'NT activity (e.g., by activators of e5'NT such as methotrexate) [350] may be a potential treatment used to improve cognitive and motor deficits, chronic inflammation associated with neurodegenerative diseases [114,351], and febrile illness [352] via A 1 receptors. Moreover, interferon-(IFN-) upregulated e5'NT expression, which may have a role in the beneficial effects of IFN-treatment in patients with multiple sclerosis via increased Ado levels-evoked enhancement of endothelial barrier function, suggesting the important neuromodulatory role of e5'NT in brain inflammation [126,[353][354][355].…”