In his long-standing interests in determining neurobiological mechanisms of adenosine, the principal investigator has constructed a novel hypothesis that release of intracellular adenosine results not only from an increase in intracellular calcium levels but also from an acidification of intracellular milieu, as measured by an decrease in intracellular pH values. This proposal will predominately use the hippocampal slice preparation to explore various aspects of adenosine neurobiology from an electrophysiological point of view.
The first aim will explore the role of intracellular pH and calcium in mediating adenosine release. These studies will explore whether changes in intracellular calcium and pH are both necessary and sufficient to produce adenosine release by using a variety of reagents which affect the intracellular milieu. The second specific aim explore whether adenosine plays an important role in regulating the basic excitability of neurons by performing experiments in adenosine A1 receptor-knockout mice. These studies will determine whether hippocampal slices from KO mice are hyperexcitable, and whether KO of adenosine A1 receptors affect the function of other inhibitory receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS029173-09A1
Application #
6335350
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Talley, Edmund M
Project Start
1991-08-01
Project End
2005-03-31
Budget Start
2001-04-13
Budget End
2002-03-31
Support Year
9
Fiscal Year
2001
Total Cost
$300,215
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Hoffman, Alexander F; Laaris, Nora; Kawamura, Masahito et al. (2010) Control of cannabinoid CB1 receptor function on glutamate axon terminals by endogenous adenosine acting at A1 receptors. J Neurosci 30:545-55
Dulla, Chris G; Frenguelli, Bruno G; Staley, Kevin J et al. (2009) Intracellular acidification causes adenosine release during states of hyperexcitability in the hippocampus. J Neurophysiol 102:1984-93
Masino, Susan A; Geiger, Jonathan D (2009) The ketogenic diet and epilepsy: is adenosine the missing link? Epilepsia 50:332-3
Masino, S A; Kawamura, M; Wasser, C D et al. (2009) Adenosine, ketogenic diet and epilepsy: the emerging therapeutic relationship between metabolism and brain activity. Curr Neuropharmacol 7:257-68
Masino, Susan A; Geiger, Jonathan D (2008) Are purines mediators of the anticonvulsant/neuroprotective effects of ketogenic diets? Trends Neurosci 31:273-8
Koranda, Jessica L; Masino, Susan A; Blaise, J Harry (2008) Bidirectional synaptic plasticity in the dentate gyrus of the awake freely behaving mouse. J Neurosci Methods 167:160-6
Gimenez-Llort, Lydia; Masino, Susan A; Diao, Lihong et al. (2005) Mice lacking the adenosine A1 receptor have normal spatial learning and plasticity in the CA1 region of the hippocampus, but they habituate more slowly. Synapse 57:8-16
Dulla, Chris G; Dobelis, Peter; Pearson, Tim et al. (2005) Adenosine and ATP link PCO2 to cortical excitability via pH. Neuron 48:1011-23
Masino, Susan A (2003) Quantitative comparison between functional imaging and single-unit spiking in rat somatosensory cortex. J Neurophysiol 89:1702-12
Masino, Susan A; Diao, Lihong; Illes, Peter et al. (2002) Modulation of hippocampal glutamatergic transmission by ATP is dependent on adenosine a(1) receptors. J Pharmacol Exp Ther 303:356-63

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