Synaptotagmin-1,-2, and-9:: Ca2+ sensors for fast release that specify distinct presynaptic properties in subsets of neurons

Synaptotagmin-1 and -2 are known Ca2+ sensors for fast synchronous neurotransmitter release, but the potential Ca2+-sensor functions of other synaptotagmins in release remain uncharacterized. We now show that besides synaptotagmin-1 and -2, only synaptotagmin-9 (also called synaptotagmin-5) mediates fast Ca2+ triggering of release. Release induced by the three different synaptotagmin Ca2+ sensors exhibits distinct kinetics and apparent Ca2+ sensitivities, suggesting that the synaptotagmin isoform expressed by a neuron determines the release properties of its synapses. Conditional knockout mice producing GFP-tagged synaptotagmin-9 revealed that synaptotagmin-9 is primarily expressed in the limbic system and striatum. Acute deletion of synaptotagmin-9 in striatal neurons severely impaired fast synchronous release without changing the size of the readily-releasable vesicle pool. These data show that in mammalian brain, only synaptotagmin-1, -2, and -9 function as Ca2+ sensors for fast release, and that these synaptotagmins are differentially expressed to confer distinct release properties onto synapses formed by defined subsets of neurons.