Multiple pathways for elevating extracellular adenosine in the rat hippocampal CA1 region characterized by adenosine sensor cells

Abstract

Extracellular adenosine in the brain, which modulates various physiological and pathological processes, fluctuates in a complicated manner that reflects the circadian cycle, neuronal activity, metabolism and disease states. The dynamics of extracellular adenosine in the brain are not fully understood, largely because of the lack of simple and reliable methods of measuring time-dependent changes in tissue adenosine distribution. This study describes the development of a biosensor, designated an adenosine sensor cell, expressing adenosine A1 receptor and a genetically-modified G protein. This biosensor was used to characterize extracellular adenosine elevation in brain tissue by measuring intracellular calcium elevation in response to adenosine. Placement of adenosine sensor cells below hippocampal slices successfully detected adenosine releases from these slices in response to neuronal activity and astrocyte swelling by conventional calcium imaging. Pharmacological analyses indicated that high-frequency electrical stimulation induced postsynaptic adenosine release in a manner dependent on L-type calcium channels and calcium-induced calcium release. Adenosine release following treatments that cause astrocyte swelling is independent of calcium channels, but dependent on aquaporin 4, an astrocyte-specific water channel subtype. The ability of ectonucleotidase inhibitors to inhibit adenosine release following astrocyte swelling, but not electrical stimulation, suggests that the former reflects astrocytic ATP release and subsequent enzymatic breakdown, whereas the latter reflects direct adenosine release from neurons. These results suggest that distinct mechanisms are responsible for extracellular adenosine elevations by neurons and astrocytes, allowing exquisite regulation of extracellular adenosine in the brain.

Adenosine receptors: Modulators of lipid availability that are controlled by lipid levels

“…Extracellular adenosine synthesis begins with the phospho-ester hydrolysis of its precursor molecule ADP or ATP, which is released by tissues (e.g., brain) (Bekar et al, 2008), electrically stimulated sensor cells (Yamashiro et al, 2017), extracellular vesicles, platelet vesicles (Weissmüller et al, 2008) and platelets in the blood (Kohli et al, 2016). ATP is rapidly converted to ADP and AMP via the enzyme ecto-nucleoside triphosphate diphosphohydrolase 1 (CD39) (Grenz et al, 2007;Köhler et al, 2007) and is further metabolized to form adenosine via ecto-5-nucleotidase (CD73) (Fredholm et al, 2007).…”

Interplay between global and pathway-specific synaptic plasticity in CA1 pyramidal cells

“…The subsequent decay of OR EPSPs to control level within minutes likely reflects restoration of tonic inhibition once A 2A Rs desensitize 67 . By contrast, A 2A R desensitization could be weaker during OR pairing than during RAD pairing, since electrical stimulation in stratum oriens elevates extracellular adenosine less than electrical stimulation in stratum radiatum 68 . Interestingly, adenosine release during OR stimulation involves L-type voltage-gated Ca 2+ channels and/or Ca 2+ -induced Ca 2+ release 68 , and could explain why a blocker of L-type voltage-gated Ca 2+ channels reduced OR pairing induced LTP.…”

“…By contrast, A 2A R desensitization could be weaker during OR pairing than during RAD pairing, since electrical stimulation in stratum oriens elevates extracellular adenosine less than electrical stimulation in stratum radiatum 68 . Interestingly, adenosine release during OR stimulation involves L-type voltage-gated Ca 2+ channels and/or Ca 2+ -induced Ca 2+ release 68 , and could explain why a blocker of L-type voltage-gated Ca 2+ channels reduced OR pairing induced LTP. Thus, distinct pathways appear capable to elevate extracellular adenosine in CA1 (NMDA in RAD and ‘Ca 2+ ’ in OR) and could be involved in the timing-dependent, asymmetric plasticity in CA1.…”

A Pattern to Link Adenosine Signaling, Circadian System, and Potential Final Common Pathway in the Pathogenesis of Major Depressive Disorder

“…Studies have revealed that both L-type calcium channels and calcium-induced calcium release can induce post-synaptic adenosine elevation [ 117 ] and that calcium signaling acts upon Per1 / 2 genes directly via CREB in mammalian cells [ 103 , 115 , 118 ]. In addition, A 1 R can also inhibit L-type calcium channels via its G i [ 3 ].…”