The modulation of adenosine by temperature, oxygen and glucose

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DESCRIPTION (provided by applicant): Adenosine is found throughout the nervous system, and its interaction with specific adenosine receptors modulates ongoing neuronal activity in many brain regions. As the core molecule of adenosine triphosphate (ATP), and a component of the overall cellular energy charge, adenosine provides a unique cellular link between energy demand and brain function. The specific inhibitory influence of the adenosine A1 receptor subtype reduces activity and helps neurons survive a short-term compromised energy supply, such as during insufficient oxygen or glucose. Its modulation of physiology and protection against pathology make adenosine a coveted therapeutic target for disorders as diverse as pain, Parkinson's disease, stroke, epilepsy, and sleep disorders. Accumulated research shows that adenosine levels are altered significantly by changes in temperature, pH, oxygen and glucose. The objective of this proposal is to elucidate the relationship between adenosine and these physiologically-relevant variables to inform and benefit both basic research and clinical conditions. The specific aims outlined herein quantify the influence of adenosine across the typical range of recording temperatures in the hippocampal slice, and systematically examine the effect(s) of reducing available oxygen and/or glucose using a combination of electrophysiology, pharmacology and genetically modified mice. Beyond the clinical significance, the proposed studies are relevant to understanding features of the model systems we use in neuroscience, and they represent a succinct set of fundamental research experiments useful as a training platform for young scientists. Ultimately, understanding the regulation of endogenous adenosine, its influence on widely used model systems, and its functional consequences during pathological conditions will enable us to explore and enhance its therapeutic possibilities in situations as diverse as stroke, epilepsy and spinal cord injury.