Synaptotagmin 7 Mediates Both Facilitation and Asynchronous Release at Granule Cell Synapses.

When an action potential invades a presynaptic terminal it evokes large, brief Ca²⁺ signals that trigger vesicle fusion within milliseconds that is followed by a small residual Ca²⁺ (Ca_res) signal. At many synapses Ca_res produces synaptic facilitation that lasts up to hundreds of milliseconds and, although less common, Ca_res can also evoke asynchronous release (AR) that persists for tens of milliseconds. The properties of facilitation and AR are very different, which suggests that they are mediated by distinct mechanisms. However, recently it has been shown that the slow calcium sensor synaptotagmin 7 (Syt7) mediates facilitation at many synapses where AR does not occur, and conversely Syt7 can mediate AR without mediating facilitation. Here we study cerebellar granule cell synapses onto stellate cells and Purkinje cells in mice of both sexes to assess the role of Syt7 in these phenomena at the same synapse. This is of particular interest at granule cell synapses where AR is much more calcium dependent and shorter-lived than facilitation. We find that Syt7 can mediate these two processes despite their divergent properties. In Syt7 knock-out animals, facilitation and AR are smaller and shorter lived than in wild-type animals, even though the initial probability of release and Ca_res signals are unchanged. Although there are short-lived Syt7-independent mechanisms that mediate facilitation and AR in Syt7 KO animals, we find that at granule cell synapses AR and facilitation are both mediated primarily by Syt7.SIGNIFICANCE At synapses made by cerebellar granule cells, presynaptic activity elevates calcium for tens of milliseconds, which in turn evokes both asynchronous release (AR) and synaptic facilitation. AR is more calcium sensitive and shorter-lived than facilitation at these synapses, suggesting that they are mediated by different mechanisms. However, we find that the slow calcium sensor synaptotagmin 7 mediates both of these phenomena. Small, rapidly decaying components of AR and facilitation are present in Syt7 KO animals, indicating that additional mechanisms can contribute to both AR and facilitation at these synapses.