Glutamate‐induced depression of EPSP–spike coupling in rat hippocampal CA1 neurons and modulation by adenosine receptors

Abstract

The presence of high concentrations of glutamate in the extracellular fluid following brain trauma or ischaemia may contribute substantially to subsequent impairments of neuronal function. In this study, glutamate was applied to hippocampal slices for several minutes, producing over-depolarisation which was reflected in an initial loss of evoked population potential size in the CA1 region. Orthodromic population spikes recovered only partially over the following 60 minutes, whereas antidromic spikes and excitatory postsynaptic potentials (epsps) showed greater recovery, implying a change in epspspike coupling (E-S coupling) which was confirmed by intracellular recording from CA1 pyramidal cells. The recovery of epsps was enhanced further by dizocilpine suggesting that the long-lasting glutamate-induced change in E-S coupling involves NMDA receptors. This was supported by experiments showing that when isolated NMDAreceptor mediated epsps were studied in isolation, there was only partial recovery following glutamate, unlike the composite epsps. The recovery of orthodromic population spikes and NMDA receptor-mediated epsps following glutamate was enhanced by the adenosine A 1 receptor blocker DPCPX, the A2A receptor antagonist SCH58261, or adenosine deaminase, associated with a loss of restoration to normal of the glutamate-induced E-S depression. The results indicate that the long-lasting depression of neuronal excitability following recovery from glutamate is associated with a depression of E-S coupling, This effect is partly dependent on activation of NMDA receptors which modify adenosine release or the sensitivity of adenosine receptors. The results may have implications for the use of A1 and A2A receptor ligands as cognitive enhancers or neuroprotectants.

Differential Effects of the Histamine H3Receptor Agonist Methimepip on Dentate Granule Cell Excitability, Paired-Pulse Plasticity and Long-Term Potentiation in Prenatal Alcohol-Exposed Rats

“…For example, blockade of NMDA receptors with dizocilpine (MK-801) reduces E-S coupling (Ferguson and Stone, 2010), and reduced GABAergic inhibition increases E-S coupling (Staff and Spruston, 2003), both effects attributed to post-synaptic mechanisms. Conversely, local dentate gyrus infusion of ghrelin, a drug that facilitates glutamate release, increases E-S coupling by affecting both pre- and post-synaptic loci (Chen et al, 2011).…”

Glutaminase 1 is a potential biomarker for chronic post-surgical pain in the rat dorsal spinal cord using differential proteomics

“…By contrast, Ca 2+ internal flow is slow, producing slow EPSPs to trigger increased excitability of secondary pain neurons and enhanced reactivity. Na + , K + and Ca 2+ influx can produce the positive feedback effect to presynaptic membranes and further increase the release of glutamate(Ferguson and Stone 2010;Kamiya and Ozawa 1998). In our study, glutaminase is the most significantly…”

Molecular probes for the A2A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold

“…Selective ligands for the adenosine receptors (ARs) are considered to have potential in the treatment of conditions of the central nervous system (CNS) [1,2]. Adenosine activates four receptor subtypes - A 1 , A 2A , A 2B , and A 3 – the first two of which have been assigned specific roles in the central nervous system [3].…”

“…A 2A AR antagonism is suggested to mediate many of the CNS stimulatory effects of caffeine in man [4]. Its blockade by potent and selective antagonists is under development as an approach to the symptomatic treatment of Parkinson's disease (PD), and such antagonists might be useful against progressive neurodegeneration [2,3,5]. The selective A 2A AR antagonists 1a , a 1,3,7-trialkylxanthine derivative, and 1b , a triazolopyrimidine derivative (Chart 1), have been in clinical trials [6,7].…”