A population of immature cerebellar parallel fibre synapses are insensitive to adenosine but are inhibited by hypoxia

Abstract

Publisher statement: "NOTICE: this is the author's version of a work that was accepted for publication in Neuropharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuropharmacology, VOL 61, ISSUE 4, 2011, DOI: 10.1016/j.neuropharm.2011 AbstractThe purine adenosine plays an important role in a number of physiological and pathological processes and is neuroprotective during hypoxia and ischemia. The major effect of adenosine is to suppress network activity via the activation of A 1 receptors. Here we report that in immature cerebellar slices, the activation of A 1 receptors has variable effects on parallel fibre synaptic transmission, ranging from zero depression to an almost complete abolition of transmission. Concentrationresponse curves suggest that the heterogeneity of inhibition stems from differences in A 1 receptor properties which could include coupling to downstream effectors. There is less variation in the effects of adenosine at parallel fibre synapses in slices from older rats and thus adenosine signalling appears developmentally regulated.In the cerebellum, hypoxia increases the concentration of extracellular adenosine leading to the activation of A 1 receptors (at adenosine-sensitive parallel fibre synapses) and the suppression of glutamate release. It would be predicted that the synapses that were insensitive to adenosine would be less depressed by hypoxia and thus maintain function during metabolic stress. However those synapses which were insensitive to adenosine were rapidly inhibited by hypoxia via a mechanism which was not reversed by blocking A 1 receptors. Thus another mechanism must be responsible for the hypoxia-mediated depression at these synapses. These different mechanisms of depression maybe important for cell survival and for maintenance of cerebellar function following oxygen starvation.3

Purinergic Signaling in the Cerebellum

“…In many of the whole-cell patch-clamp experiments, recordings were made with Cs+ in the pipette, which will block postsynaptic GIRK channels (e.g., see Courjaret et al 2009). In our hands, we found that adenosine had no effect on the firing rate of Purkinje cells (recorded with an extracellular electrode), although activation of GABA B receptors markedly reduced the firing rate (Atterbury and Wall 2011). This contrasts with the findings of Kessler et al (2008) who found in organotypic cerebellar slices that A 1 receptor agonists reduce the firing rate of Purkinje cells and the original findings of Dunwiddie et al (1984) in acute slices and in vivo.…”

Intersaccadic drift velocity is sensitive to short‐term hypobaric hypoxia

“…Accordingly, studies have shown that the cerebellum plays an important role in gaze holding (Leigh & Zee, ; Bertolini et al ., ). Because hypoxia induces alterations in the metabolic system of the cerebellum (Serrano et al ., ; Atterbury & Wall, ), it may increase eye instability by disrupting the cerebellar inputs to the neural integrator (Zee et al ., ; Eizenman et al ., ; Aksay et al ., ).…”