Activation of Synaptic NMDA Receptors by Action Potential-Dependent Release of Transmitter during Hypoxia Impairs Recovery of Synaptic Transmission on Reoxygenation

Abstract

Increased levels of glutamate and the subsequent activation of NMDA receptors are responsible for neuronal damage that occurs after an ischemic or hypoxic episode. In the present work, we investigated the relative contribution of presynaptic and postsynaptic blockade of synaptic transmission, as well as of blockade of NMDA receptors, for the facilitation of recovery of synaptic transmission in the CA1 area of rat hippocampal slices exposed to prolonged (90 min) hypoxia. During hypoxia, there was a complete inhibition of field EPSPs, which was fully reversible if released adenosine was allowed to act. When adenosine A(1) receptors were blocked with the selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), recovery of synaptic transmission from hypoxia was significantly attenuated, and this impairment could be overcome by preventing synaptic transmission during hypoxia either with tetrodotoxin (TTX) or by switching off the afferent stimulation but not by postsynaptic blockade of transmission with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or selective blockade of adenosine A(2A) receptors. When synaptic transmission was allowed to occur during hypoxia, because of the presence of DPCPX, there was an NMDA receptor-mediated component of the EPSCs recorded in CA1 pyramidal neurons, and blockade of NMDA receptors with AP-5 restored recovery of synaptic transmission from hypoxia. It is concluded that impairment of recovery of synaptic transmission after an hypoxic insult results from activation of synaptic NMDA receptors by synaptically released glutamate and that adenosine by preventing this activation efficiently facilitates recovery.

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

“…Our results do not support such a mechanism because (i) the selective A 3 receptor antagonist MRS1523 not only does not potentiate fEPSP inhibition induced by 2-and 5-min OGD but attenuates this effect and (ii) Cl-IB-MECA protects against AD appearance and irreversible disruption of excitatory neurotransmission caused by prolonged (7-min) OGD episodes, whereas A 1 antagonism shortens the onset of AD evoked by hypoxia [43].…”

“…Unlike the A 3 antagonists, the selective A 1 receptor antagonist DPCPX impairs the recovery of synaptic potentials after a hypoxic insult [43]. In rats in vivo the nonselective adenosine receptor antagonist theophylline increases the incidence of spreading depression, the analogue of AD in normoxic conditions, and decreases the latency of spreading-depression occurrence elicited by microdialysis of high K + perfusate through the hippocampal CA1 area [44].…”

Interleukin-6 Upregulates Neuronal Adenosine A1 Receptors: Implications for Neuromodulation and Neuroprotection

“…The inhibition of synaptic transmission in the hippocampus is crucial to protect neurons from excitotoxicity induced by neuropathological events, such as hypoxia. Under such conditions, considerable amounts of adenosine are released and operate A 1 receptors to restrain synaptic glutamate release (Sebastião et al, 2001). Thus, we tested the effect of brief (3 min) hypoxic episodes in fEPSPs recorded from control and IL-6-treated slices.…”

“…We have previously shown that IL-6 induces the upregulation of mRNA transcripts for the adenosine A 1 receptor in the brain (Biber et al, 2001). Functional adenosine A 1 receptors fulfill important neuroprotective properties during excitotoxic conditions, causing the inhibition of glutamate release from the presynaptic terminal (Barrie and Nicholls, 1993), the downregulation of postsynaptic NMDA receptor-mediated currents (de Mendonça et al, 1995;Sebastião et al, 2001) and the stabilization of the postsynaptic cell membrane (Trussell and Jackson, 1985;Gerber and Gahwiler, 1994). Despite the fact that adenosine A 1 receptor has been recurrently discussed as a potential target for the treatment of neurodegenerative diseases (Ribeiro, 2005), adenosine A 1 receptor agonists are not used with therapeutic purposes, mostly due to prominent peripheral side effects, short half-lives, and/or receptor desensitization (Yan et al, 2003;Stone, 2002;Dalpiaz and Manfredini, 2002).…”

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…However, in more simplified models of neuronal dysfunction, it was not possible to confirm that the presynaptic modulation of glutamate release by A 2A Rs was related to their control of neuronal damage. In fact, when studying hypoxia-or ischemia-induced depression of synaptic transmission, where the presynaptic control of glutamate release is related to the post-hypoxic recovery of synaptic transmission (see [259]), blockade of A 2A Rs is essentially devoid of effects [259,260]. An interesting alternative to reconcile the control of extracellular glutamate levels by A 2A Rs with the neuroprotective role of A 2A R blockade would be a control by A 2A Rs of the release and clearance of glutamate by astrocytes.…”