title: Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture.
abstract: Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines.
authors.affiliation: From the Department of Neurobiology, Interdisciplinary Centre for Neurosciences, University of Heidelberg, INF 364, 69120 Heidelberg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Mauceri
authors.affiliation: From the Department of Neurobiology, Interdisciplinary Centre for Neurosciences, University of Heidelberg, INF 364, 69120 Heidelberg, Germany.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Hagenston
authors.affiliation: From the Department of Neurobiology, Interdisciplinary Centre for Neurosciences, University of Heidelberg, INF 364, 69120 Heidelberg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schramm
authors.affiliation: From the Department of Neurobiology, Interdisciplinary Centre for Neurosciences, University of Heidelberg, INF 364, 69120 Heidelberg, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Weiss
authors.affiliation: From the Department of Neurobiology, Interdisciplinary Centre for Neurosciences, University of Heidelberg, INF 364, 69120 Heidelberg, Germany Hilmar.Bading@uni-hd.de.
authors.forename: Hilmar
authors.initials: H
authors.lastname: Bading
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015922:Complement C1q / Q000096:biosynthesis; D049229:Dendritic Spines / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009415:Nerve Net / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis
chemical_list: D042643:Vascular Endothelial Growth Factor D; D015922:Complement C1q; D002118:Calcium
keywords: calcium; calcium binding protein; dendrite; gene expression; signal transduction; synapse