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 (A2AR) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2AR 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 A2AR facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A2AR enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A2AR has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A2AR 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 A2AR 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 A2AR effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A2AR's facilitatory effect on cortical network activity. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc.