Synaptotagmins 3 and 7 mediate the majority of asynchronous release from synapses in the cerebellum and hippocampus.

Neurotransmitter release consists of rapid synchronous release followed by longer-lasting asynchronous release (AR). Although the presynaptic proteins that trigger synchronous release are well understood, the mechanisms for AR remain unclear. AR is sustained by low concentrations of intracellular Ca2+ and Sr2+, suggesting the involvement of sensors with high affinities for both ions. Synaptotagmin 7 (SYT7) partly mediates AR, but substantial AR persists in the absence of SYT7. The closely related SYT3 binds Ca2+ and Sr2+ with high affinity, making it a promising candidate to mediate AR. Here, we use knockout mice to study the contribution of SYT3 and SYT7 to AR at cerebellar and hippocampal synapses. AR is dramatically reduced when both isoforms are absent, which alters the number and timing of postsynaptic action potentials. Our results confirm the long-standing prediction that SYT3 mediates AR and show that SYT3 and SYT7 act as dominant mechanisms for AR at three central synapses.

Effects of psilocybin on uncertain punishment learning.

Psilocybin may provide a useful treatment for mood disorders including anxiety and depression but its mechanisms of action for these effects are not well understood. While recent preclinical work has begun to assess psilocybin's role in affective behaviors through innate anxiety or fear conditioning, there is scant evidence for its role in conflict between reward and punishment. The current study was designed to determine the impact of psilocybin on the learning of reward-punishment conflict associations, as well as its effects after learning, in male and female rats. We utilized a chained schedule of reinforcement that involved execution of safe and risky reward-guided actions under uncertain punishment. Different patterns of behavioral suppression by psilocybin emerged during learning versus after learning of risky action-reward associations. Psilocybin increased behavioral suppression in female rats as punishment associations were learned. After learning, psilocybin decreased behavioral suppression in both sexes. Thus, psilocybin produces divergent effects on action suppression during approach-avoidance conflict depending on when the conflict is experienced. This observation may have implications for its therapeutic mechanism of action.