Working memory and the homeostatic control of brain adenosine by adenosine kinase

Abstract

The neuromodulator adenosine maintains brain homeostasis and regulates complex behaviour via activation of inhibitory and excitatory adenosine receptors (ARs) in a brain region-specific manner. AR antagonists such as caffeine have been shown to ameliorate cognitive impairments in animal disease models but their effects on learning and memory in normal animals are equivocal. An alternative approach to reduce AR activation is to lower the extracellular tone of adenosine, which can be achieved by up-regulating adenosine kinase (ADK), the key enzyme of metabolic adenosine clearance. However, mice that globally over-express an Adk transgene (‘Adk-tg’ mice) were devoid of a caffeine-like pro-cognitive profile; they instead exhibited severe spatial memory deficits. This may be mechanistically linked to cortical/hippocampal N-methyl-D-aspartate receptor (NMDAR) hypofunction because the motor response to acute MK-801 was also potentiated in Adk-tg mice. Here, we evaluated the extent to which the behavioural phenotypes of Adk-tg mice might be modifiable by up-regulating adenosine levels in the cortex/hippocampus. To this end, we investigated mutant ‘fb-Adk-def’ mice in which ADK expression was specifically reduced in the telencephalon leading to a selective increase in cortical/hippocampal adenosine, while the rest of the brain remained as adenosine-deficient as in Adk-tg mice. The fb-Adk-def mice showed an even greater impairment in spatial working memory and a more pronounced motor response to NMDAR blockade than Adk-tg mice. These outcomes suggest that maintenance of cortical/hippocampal adenosine homeostasis is essential for effective spatial memory and deviation in either direction is detrimental with increased expression seemingly more disruptive than decreased expression.

Deletion of Adenosine A2A Receptors From Astrocytes Disrupts Glutamate Homeostasis Leading to Psychomotor and Cognitive Impairment: Relevance to Schizophrenia

“…Horizontal locomotor activity was analyzed in polypropylene cages placed into adjustable frames equipped with seven infrared photocell beams (San Diego Instruments) (32). Working and reference memories were evaluated using the Y-maze spontaneous alternation test and the 8-baited-arms radial arm maze test, as previously described (32,42,51). …”

Adenosine Kinase, a Common Pathologic Biomarker for Human Pharmacoresistant Epilepsy

“…As a critical upstream regulator of complex homeostatic and metabolic networks, ADK has been demonstrated to play a crucial role in the regulation of cognition process. ADK-tg mice, with transgenic overexpression of ADK in the brain, demonstrated a series of cognition deficits [60,67]. ADK overexpression has been proved to lead to functional concomitant alterations in dopaminergic and glutamatergic functions.…”

Adenosine Kinase: Exploitation for Therapeutic Gain

“…As an upstream regulator of major neurotransmitter systems, including glutamatergic neurotransmission (Sebastiao and Ribeiro, 2009b;Ribeiro and Sebastiao, 2010;Diógenes et al, 2012), adenosine is a prime candidate for the modulation of cognitive processes. Importantly, transgenic overexpression of ADK in the brain of mice (Adk-tg mice) caused prominent cognitive impairment on several levels (Yee et al, 2007;Singer et al, 2012). The motor stimulant effect of MK-801 was potentiated in Adk-tg mice suggesting N-methyl-D-aspartate receptor hypofunction (Yee et al, 2007).…”