ASTROGLIAL PANNEXIN 1 SETS HIPPOCAMPAL NEURONAL NETWORK PATTERNS
Elena Dossi1, Flora Vasile1, Julien Moulard1, Marc Le Bert2, Isabelle Couillin2, Alexis Bemelmans3, Nathalie Rouach1
Astroglial release of molecules is thought to actively modulate neuronal activity, but the nature, release pathway and cellular target of these neuroactive molecules are still unclear. Pannexin-1, a member of the Px family of proteins, form functional, high conductance, non-selective transmembrane channels, which are expressed in neurons as well as in astrocytes and which mediate extracellular exchange of molecules. They are not active at rest but open in response to membrane potential changes, mechanical stretch and high extracellular potassium and ATP concentrations. Their functional relevance has been mostly studied in neurons or regardless of cell types. However, our knowledge of astroglial pannexin-1 regulation and control of neuronal activity remains very limited, due to the lack of tools targeting these channels in a cell-specific way. We here show that astroglial pannexin-1 expression is developmentally regulated, and that its activation is activity-dependent. By using an astroglial Px1-deficient transgenic mouse, we found that such astroglial pannexin-1 channels activation, in contrast to the overall effect of pannexin-1 activation in all cell types, selectively and negatively regulates hippocampal networks as their disruption induces a drastic switch from bursts to paroxysmal activity. This effect, which is associated with an increased excitability of hippocampal pyramidal cells and a reduction in ATP release, occurs via an unconventional astroglial mechanism controlling hyperpolarisation-activated cyclic nucleotide-gated channels. We thus reveal astroglial pannexin-1 channel activation as a negative feedback loop mechanism crucial for the inhibition of hippocampal neuronal networks.