Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus.
Adenosine inhibits excitatory neurons widely in the brain through adenosine A1 receptor, but activation of adenosine A2A receptor (A2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2A R expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A2A R enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A2A R has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A2A R activation alters the synaptic excitation - inhibition balance in the CA1 area resulting in increased pyramidal cell discharge to glutamatergic Schaffer collateral stimulation. In line with this, we show that A2A R promotes synchronous pyramidal cell firing in hyperexcitable conditions where extracellular potassium is elevated or following high-frequency electrical stimulation. Our results revealed selective synapse- and cell type specific adenosine A2A R effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A2A R's facilitatory effect on cortical network activity.
Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Portugal; Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Portugal; Department of Pharmacology, Oxford University, Oxford, United Kingdom.
Diogo M
DM
Rombo
Kathryn
K
Newton
Wiebke
W
Nissen
Sylvia
S
Badurek
Jacqueline M
JM
Horn
Liliana
L
Minichiello
John G R
JG
Jefferys
Ana M
AM
Sebastiao
Karri P
KP
Lamsa
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D062308:Optogenetics; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D043705:Receptor, Adenosine A2A; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011188:Potassium
antiepileptic; basket cell; cholecystokinin; disinhibition; parvalbumin; synchrony