AU  - Kaeser-Woo, Yea Jin
AU  - Younts, Thomas J.
AU  - Yang, Xiaofei
AU  - Zhou, Peng
AU  - Wu, Dick
AU  - Castillo, Pablo E.
AU  - Südhof, Thomas C.
TI  - Synaptotagmin-12 Phosphorylation by cAMP-Dependent Protein Kinase Is Essential for Hippocampal Mossy Fiber LTP
PT  - JOURNAL ARTICLE
DP  - 2013 Jun 05 
TA  - The Journal of Neuroscience 
PG  - 9769-9780 
VI  - 33 
IP  - 23 
4099 - http://www.jneurosci.org/content/33/23/9769.abstract 
4100 - http://www.jneurosci.org/content/33/23/9769.full 
SO - J. Neurosci. 2013 Jun 05; 33(23):9769-9780 
AID  - 10.1523/JNEUROSCI.5814-12.2013 [doi] 
AB  - Synaptotagmin-12 (Syt12) is an abundant synaptic vesicle protein that—different from other synaptic vesicle-associated synaptotagmins—does not bind Ca2+. Syt12 is phosphorylated by cAMP-dependent protein kinase-A at serine-97 in an activity-dependent manner, suggesting a function for Syt12 in cAMP-dependent synaptic plasticity. To test this hypothesis, we here generated (1) Syt12 knock-out mice and (2) Syt12 knockin mice carrying a single amino-acid substitution [the serine-97-to-alanine- (S97A)-substitution]. Both Syt12 knock-out mice and Syt12 S97A-knockin mice were viable and fertile, and exhibited no measurable change in basal synaptic strength or short-term plasticity as analyzed in cultured cortical neurons or in acute hippocampal slices. However, both Syt12 knock-out and Syt12 S97A-knockin mice displayed a major impairment in cAMP-dependent mossy-fiber long-term potentiation (LTP) in the CA3 region of the hippocampus. This impairment was observed using different experimental configurations for inducing and monitoring mossy-fiber LTP. Moreover, although the Syt12 knock-out had no effect on the short-term potentiation of synaptic transmission induced by the adenylate–cyclase activator forskolin in cultured cortical neurons and in the CA1 region of the hippocampus, both the Syt12 knock-out and the Syt12 S97A-knockin impaired the long-term increase in mossy-fiber synaptic transmission induced by forskolin. Thus, Syt12 is essential for cAMP-dependent presynaptic LTP at mossy-fiber synapses, and a single amino-acid substitution that blocks the cAMP-dependent phosphorylation of Syt12 is sufficient to impair the function of Syt12 in mossy-fiber LTP, suggesting that cAMP-dependent phosphorylation of Syt12 on serine-97 contributes to the induction of mossy-fiber LTP.