Abstract
Doc2a and Doc2b are high-affinity calcium-binding proteins that interact with SNARE proteins and phospholipids. Experiments performed on cultured cells indicated that Doc2 proteins promote spontaneous vesicle fusion and asynchronous neurotransmitter release, regulate vesicle priming, mediate augmentation, and regulate transmission during sustained activity. Here, we assess the role of Doc2 proteins in synaptic transmission under physiological conditions at mature synapses made by Purkinje cells onto neurons in the deep cerebellar nuclei (PC to DCN synapses). PCs express Doc2b but not Doc2a. Surprisingly, spontaneous neurotransmitter release, synaptic strength, the time course of evoked release, responses evoked by sustained high-frequency stimulation, and short-term plasticity were normal in Doc2b KO mice. Thus, in stark contrast to numerous functions previously proposed for Doc2, here we find that Doc2b removal does not influence transmission at PC-to-DCN synapses, indicating that conclusions based on studies of Doc2b in cultured cells do not necessarily generalize to mature synapses under physiological conditions.
Highlights
Presynaptic calcium signaling plays a critical role in neurotransmitter release and synaptic plasticity
In order to assess the suitability of the Purkinje cell (PC) to Deep Cerebellar Nuclei (DCN) synapse for our studies, we used fluorescence in situ hybridization (FISH) to evaluate Doc2b and Doc2a gene expression in adult (P60-P70) wildtype and Doc2b KO mice (Groffen et al, 2010)
These studies indicate that Doc2b is the only calcium-dependent Doc2 present at PC synapses of adult wildtype mice, that it is eliminated in Doc2b KO mice, and that there is no compensatory expression of Doc2a in PCs of Doc2b KO mice
Summary
Presynaptic calcium signaling plays a critical role in neurotransmitter release and synaptic plasticity. Of particular interest are proteins that contain tandem C2 domains that bind Ca and interact with phospholipids and SNARE proteins, such as several Ca-sensitive Synaptotagmin isoforms (Syts) and two Doc isoforms, Doc2a and Doc2b (Groffen et al, 2010; Pang et al, 2011; Yao et al, 2011) Some of these proteins (Syt and Syt2) bind calcium with low affinity and fast kinetics to mediate fast synaptic transmission (Fernandez-Chacon et al, 2001). Others, such as Syt, bind Ca with high affinity and slow kinetics and mediate facilitation and asynchronous neurotransmitter release (Wen et al, 2010; Jackman et al, 2016). Doc2b and Doc2a bind calcium with high affinity, but their contribution to synaptic transmission is unclear
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