Synaptic mechanisms of adenosine A_2A receptor‐mediated hyperexcitability in the hippocampus

Abstract

Adenosine inhibits excitatory neurons widely in the brain through adenosine A 1 receptor, but activation of adenosine A 2A receptor (A 2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A 2A 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 A 2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A 2A R enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A 2A R has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A 2A 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 A 2A 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 A 2A R effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A 2A R's facilitatory effect on cortical network activity.

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

“…In conclusion, upregulation of A 2A receptors localized in hippocampal astrocytes of drug-resistant MTLE human patients suggest that blockade of these receptors with selective antagonists may prevent neuronal excitation and confer neuroprotection, as previously documented in epileptic animal models [10,21,22,26]. Therefore, the hippocampal astrocytic A 2A receptor may be an attractive pharmacological target to increase seizure threshold and manage therapeutically drugrefractory MTLE in alternative to the pure neurocentric view that dominated antiepileptic drugs research for decades [67].…”

“…Thus, involvement of the A 2A receptor in diverse pathologies of the central nervous system, including epilepsy [17][18][19][20][21][22][23][24][25], may be due to counteraction of the neuroprotective role of adenosine via the A 1 receptor [24]. Most studies demonstrating the proconvulsive effect of the A 2A receptor have been performed in rodents, both in mice [17][18][19]26] and rats [20][21][22][23][24]. Results from these investigations suggest that selective A 2A receptor antagonists might offer protection against diverse epileptic syndromes, such as temporal lobe epilepsy, highlighting the idea that the A 2A receptor may be an attractive pharmacological target for the treatment of epilepsy.…”

BDNF-induced presynaptic facilitation of GABAergic transmission in the hippocampus of young adults is dependent of TrkB and adenosine A2A receptors

“…Interestingly, as we now show, the presynaptic influence of TrkB receptors upon GABA release at GABAergic synapses is also under control of tonic adenosine A 2A R activation since the BDNF-induced increase on mIPSC frequency was prevented in the presence of an adenosine A 2A R antagonist. Remarkably, A 2A Rs, though present in a subset of GABAergic nerve terminals, do not directly affect GABAergic inputs to pyramidal neurons [35], but as we now show, they can do so in an indirect way by allowing facilitatory BDNF actions in GABAergic nerve terminals.…”

“…We thus hypothesized that A 2A R, in spite of disynaptically modulating GABAergic transmission to pyramidal cells [35], could directly affect the monosynaptic action of BDNF to principal cells. We thus tested whether endogenous activation of adenosine A 2A R could also influence the action of BDNF on GABAergic transmission.…”

Adenosine A2A receptor activation is determinant for BDNF actions upon GABA and glutamate release from rat hippocampal synaptosomes

“…Thus in our case, the A 2A R ligands were used as modifier drugs being present throughout the release period (during both S1 and S2), thus not affecting the S2/S1 ratios. Interestingly, the influence of A 2A Rs on GABA release at the hippocampus is synapse-and cell type-selective [24]. As we now show, A 2A R also contributes to BDNF-mediated inhibition of GABA release; this action of BDNF being known to result from GABA transporters modulation [16].…”