Abstract
It is well described that A1 adenosine receptors inhibit synaptic transmission at excitatory synapses in the brain, but the effect of adenosine on reciprocal synapses has not been studied so far. In the olfactory bulb, the majority of synapses are reciprocal dendro-dendritic synapses mediating recurrent inhibition. We studied the effect of A1 receptor activation on recurrent dendro-dendritic inhibition in mitral cells using whole-cell patch-clamp recordings. Adenosine reduced dendro-dendritic inhibition in wild-type, but not in A1 receptor knock-out mice. Both NMDA receptor-mediated and AMPA receptor-mediated dendro-dendritic inhibition were attenuated by adenosine, indicating that reciprocal synapses between mitral cells and granule cells as well as parvalbumin interneurons were targeted by A1 receptors. Adenosine reduced glutamatergic self-excitation and inhibited N-type and P/Q-type calcium currents, but not L-type calcium currents in mitral cells. Attenuated glutamate release, due to A1 receptor-mediated calcium channel inhibition, resulted in impaired dendro-dendritic inhibition. In behavioral tests we tested the ability of wild-type and A1 receptor knock-out mice to find a hidden piece of food. Knock-out mice were significantly faster in locating the food. Our results indicate that A1 adenosine receptors attenuates dendro-dendritic reciprocal inhibition and suggest that they affect odor information processing.
Highlights
ATP and its metabolites, ADP and adenosine, are neurotransmitters and neuromodulators acting in virtually all brain areas (Illes et al, 1996; Burnstock et al, 2011; Burnstock, 2013)
Little is known so far about the impact of adenosine on synaptic transmission at reciprocal synapses. To address this issue we studied the effect of adenosine on recurrent dendro-dendritic inhibition (DDI) of mitral cells in the mouse olfactory bulb
Upon addition of tetrodotoxin citrate (TTX) and CTZ and withdrawal of Mg2+, the recorded DDI integral of −105.9 ± 21.9 nA∗ms (n = 13) increased to −1162.8 ± 145.8 nA∗ms (n = 13, p = 6.5∗10−6), reflecting substantial GABA release by interneurons connected to the recorded mitral cell by reciprocal synapses (Figures 1C,D)
Summary
ATP and its metabolites, ADP and adenosine, are neurotransmitters and neuromodulators acting in virtually all brain areas (Illes et al, 1996; Burnstock et al, 2011; Burnstock, 2013). ATP is released as cotransmitter during calcium-dependent exocytosis (Pankratov et al, 2006; Zhang et al, 2007; Thyssen et al, 2010), activates postsynaptic receptors and is degraded by extracellular enzymes to give rise to ADP, AMP and adenosine (Dunwiddie et al, 1997; Sebastiao et al, 1999; Zimmermann, 2000; Zimmermann et al, 2012) Those purine-degrading extracellular enzymes are divided into different groups, amongst others containing ecto-5 -nuclotidase (CD73) and alkaline. The activity of tissue non-specific alkaline phosphatase is very high in this brain region (Langer et al, 2008) This suggests a prominent role of purinergic signaling in the olfactory bulb, especially for ATP metabolites such as adenosine. Activation of A2A receptors facilitates transmitter release (Okada et al, 1992; Mogul et al, 1993; Wirkner et al, 2004)
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