- The mitochondrial solute carrier family 8 sodium/calcium/lithium exchanger, member B1 (NCLX) is an important mediator of calcium extrusion from mitochondria. In this study, we tested the hypothesis that physiological expression levels of NCLX are essential for maintaining neuronal resilience in the face of excitotoxic challenge. Using an shRNA-mediated approach, we showed that reduced NCLX expression exacerbates neuronal mitochondrial calcium dysregulation, mitochondrial membrane potential (ΔΨm) breakdown, and reactive oxygen species generation during excitotoxic stimulation of primary hippocampal cultures.
- Nucleo-cytoplasmic shuttling of class IIa histone deacetylases (i.e. HDAC4, -5, -7, and -9) is a synaptic activity- and nuclear calcium–dependent mechanism important for epigenetic regulation of signal-regulated gene expression in hippocampal neurons. HDAC4 in particular has been linked to the regulation of genes important for both synaptic structure and plasticity. Here, using a constitutively nuclear-localized, dominant-active variant of HDAC4 (HDAC4 3SA), we demonstrate that HDAC4 accumulation in the nucleus severely reduces both the length and complexity of dendrites of cultured mature hippocampal neurons, but does not affect the number of dendritic spines.
- Synaptic activity drives changes in gene expression to promote long lasting adaptations of neuronal structure and function. One example of such an adaptive response is the buildup of acquired neuroprotection, a synaptic activity- and gene transcription-mediated increase in the resistance of neurons against harmful conditions. A hallmark of acquired neuroprotection is the stabilization of mitochondrial structure and function. We therefore re-examined previously identified sets of synaptic activity-regulated genes to identify genes that are directly linked to mitochondrial function.
- Background: Calcium-binding proteins regulate calcium dynamics and downstream signaling events.Results: Increasing the calcium buffering capacity of the nucleus alters the expression of genes that regulate neuronal architecture.Conclusion: The nuclear calcium buffering capacity is an important determinant of neuronal morphology.Significance: Nuclear calcium buffers represent a new target for modulating gene expression and neuronal structure.