Calcium spikes accompany cleavage furrow ingression and cell separation during fission yeast cytokinesis

Calcium rises transiently at the division plane during cytokinesis of embryonic cells, but the conservation and function of such calcium transients remain unclear. We discovered similar calcium spikes during fission yeast cytokinesis, and demonstrated that calcium promotes contractile ring constriction and daughter cell integrity.

REM sleep promotes experience-dependent dendritic spine elimination in the mouse cortex

In many parts of the nervous system, experience-dependent refinement of neuronal circuits predominantly involves synapse elimination. The role of sleep in this process remains unknown. We investigated the role of sleep in experience-dependent dendritic spine elimination of layer 5 pyramidal neurons in the visual (V1) and frontal association cortex (FrA) of 1-month-old mice. We found that monocular deprivation (MD) or auditory-cued fear conditioning (FC) caused rapid spine elimination in V1 or FrA, respectively. MD- or FC-induced spine elimination was significantly reduced after total sleep or REM sleep deprivation. Total sleep or REM sleep deprivation also prevented MD- and FC-induced reduction of neuronal activity in response to visual or conditioned auditory stimuli. Furthermore, dendritic calcium spikes increased substantially during REM sleep, and the blockade of these calcium spikes prevented MD- and FC-induced spine elimination. These findings reveal an important role of REM sleep in experience-dependent synapse elimination and neuronal activity reduction.

Calcium spikes accompany the cleavage furrow ingression and cell separation during fission yeast cytokinesis

The role of calcium signaling during cytokinesis has long remained ambiguous. The studies of embryonic cell division discovered that calcium concentration increases transiently at the division plane just before the cleavage furrow ingression, leading to the hypothesis that these calcium transients trigger the contractile ring constriction. However, such calcium transients have only been found in animal embryos and their function remains controversial. Here we explored cytokinetic calcium transients in the model organism fission yeast. We adopted GCaMP, a genetically encoded calcium indicator, to determine the intracellular calcium level. We validated GCaMP as a highly sensitive calcium indicator which allowed us to capture the calcium transients stimulated by osmotic shocks. To identify calcium transients during cytokinesis, we first identified a correlation between the intracellular calcium level and cell division. Next, we discovered calcium spikes at the start of the cleavage furrow ingression and the end of the cell separation using time-lapse microscopy to. Inhibition of these calcium spikes slowed down the furrow ingression and led to frequent lysis of the daughter cells. We conclude that like the larger animal embryos fission yeast triggers cytokinetic calcium transients which promote the ring constriction and daughter cell integrity (194).Highlight summary for TOCCalcium rises transiently at the division plane during embryonic cell cytokinesis, but the conservation and function of such calcium transients remain unclear. We identified similar calcium spikes during fission yeast cytokinesis and demonstrated that these spikes promote the contractile ring constriction and the daughter cell integrity (257).

Neurogranin Stimulates Ca2+/calmodulin-dependent Kinase II by Inhibiting Calcineurin at Specific Calcium Spike Frequencies

Calmodulin sits at the centre of molecular mechanisms underlying learning and memory. Its complex, and sometimes opposite influences, via the binding to various proteins, are yet to be fully understood. Calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) both bind open calmodulin, favouring Long-term potentiation (LTP) or depression (LTD) respectively. Neurogranin binds to the closed conformation of calmodulin and its impact on synaptic plasticity is less clear. We set up a mechanistic computational model based on allosteric principles to simulate calmodulin state transitions and its interaction with calcium ions and the three binding partners mentioned above. We simulated calcium spikes at various frequencies and show that neurogranin regulates synaptic plasticity along three modalities. At low spike frequencies, neurogranin inhibits the onset of LTD by limiting CaN activation. At intermediate frequencies, neurogranin limits LTP by precluding binding of CaMKII with calmodulin. Finally, at high spike frequencies, neurogranin promotes LTP by enhancing CaMKII autophosphorylation. While neurogranin might act as a calmodulin buffer, it does not significantly preclude the calmodulin opening by calcium. On the contrary, neurogranin synchronizes the opening of calmodulin’s two lobes and promotes their activation at specific frequencies, increasing the chance of CaMKII trans-autophosphorylation. Taken together, our study reveals dynamic regulatory roles played by neurogranin on synaptic plasticity, which provide mechanistic explanations to opposing experimental findings.Author SummaryHow our brains learn and remember things lies in the subtle changes of the strength with which brain cells connect to each other, the so-called synaptic plasticity. At the level of the recipient neuron, some of the information is encoded into patterns of intracellular calcium spikes. Calmodulin, a small bilobed protein which conformation is regulated by the binding of calcium ions, decodes these signals, and modulates the activity of specific binding partners.Two key regulators, calcineurin and calcium/calmodulin-dependent protein kinase II, which respectively weaken or strengthen synaptic connections, bind both lobes of calmodulin in its open form, favoured by calcium. On the contrary, neurogranin binds preferentially to one lobe of calmodulin, in the closed form, unfavoured by calcium. It was thus initially suggested that it would inhibit calmodulin activation and decrease synaptic plasticity. However, past research showed that neurogranin sometimes actually enhances synaptic plasticity, though the mechanism was unclear.Our computational models showed that neurogranin synchronizes the activation of the two lobes of calmodulin, favouring opening at high frequency calcium spikes. By doing so, neurogranin increases the impact of calmodulin on calcium/calmodulin-dependent protein kinase II and reduces its effect on calcineurin, resulting in a strengthening of synaptic connections.