Synaptic Activity Induces Dramatic Changes in the Geometry of the Cell Nucleus: Interplay between Nuclear Structure, Histone H3 Phosphorylation, and Nuclear Calcium Signaling

Abstract

Synaptic activity initiates many adaptive responses in neurons. Here we report a novel form of structural plasticity in dissociated hippocampal cultures and slice preparations. Using a recently developed algorithm for three-dimensional image reconstruction and quantitative measurements of cell organelles, we found that many nuclei from hippocampal neurons are highly infolded and form unequally sized nuclear compartments. Nuclear infoldings are dynamic structures, which can radically transform the geometry of the nucleus in response to neuronal activity. Action potential bursting causing synaptic NMDA receptor activation dramatically increases the number of infolded nuclei via a process that requires the ERK-MAP kinase pathway and new protein synthesis. In contrast, deathsignaling pathways triggered by extrasynaptic NMDA receptors cause a rapid loss of nuclear infoldings. Compared with near-spherical nuclei, infolded nuclei have a larger surface and increased nuclear pore complex immunoreactivity. Nuclear calcium signals evoked by cytosolic calcium transients are larger in small nuclear compartments than in the large compartments of the same nucleus; moreover, small compartments are more efficient in temporally resolving calcium signals induced by trains of action potentials in the theta frequency range (5 Hz). Synaptic activity-induced phosphorylation of histone H3 on serine 10 was more robust in neurons with infolded nuclei compared with neurons with near-spherical nuclei, suggesting a functional link between nuclear geometry and transcriptional regulation. The translation of synaptic activity-induced signaling events into changes in nuclear geometry facilitates the relay of calcium signals to the nucleus, may lead to the formation of nuclear signaling microdomains, and could enhance signal-regulated transcription.

Structural dynamics of the cell nucleus

“…Infolded nuclei are better at resolving high frequency stimuli. 3 Here we show, that the measure A nuc is also strongly affected by frequency (Fig. 4).…”

“…One observation described in Wittmann et al (2009) concerns the size of the nuclear envelope, which increases with the degree of nuclear infoldings. The increase in nuclear surface is proportional to an increase in NPCs immunoreactivity; an increased number of NPCs can accelerate calcium entry into infolded nuclei.…”

“…As mentioned above, in the study by Wittmann et al (2009) we demonstrated that enlargement of membrane surface area is accompanied by increased immunoreactivity for NPCs. 3 In their function as 'flood gates' for nuclear calcium, an increased number of nuclear pore complexes will make the nuclear envelope more permeable. 4,5 Notably, the generation of signaling microdomains in the nucleus in conjunction with increased surface expression of nuclear pores will not only facilitate nuclear signaling of calcium-as outlined above-but it will also augment nuclear signaling of second messengers in general 3,6 (Fig.…”

Image Informatics Strategies for Deciphering Neuronal Network Connectivity

“…They can adopt shapes that range from near spherical to complex and highly folded, and this is correlated with neuronal activity 64 . Nuclear folding has been suggested to be necessary for relaying calcium signals to the nucleus, which is fundamental for proper gene expression 1 .…”

“…As far as the internal nuclear structure is concerned, phenomena, such as folding, have been addressed far less. Nuclear folds are generally visualized using stains for the nuclear lamina and analysed using procedures that often include manual assessment 64,65 . To describe the internal structure of nuclei in more objective terms, an automatic image analysis procedure has been developed 66 that quantifies the 3D internal structure of nuclei on the basis of a nuclear lamina stain using three descriptors: mean intensity, skewness and mean curvature.…”