The first, and up to now the only available, hint of altered purinergic signaling in DS came indirectly from the observation that lack of sortin nexin 27 (SNX27), a PDZ-containing protein of the endosome-associated retromer complex controlling the trafficking of several proteins (Carlton et al., 2005), leads to severe impairment of brain functions, including cognitive manifestations mimicking those observed in DS (Wang et al., 2013, 2014). The gene discussed is SNX27; the disease is Dravet syndrome.