Neuronal Calcium Signalling: From Synaptic Microdomains to Nuclear Gene Programs

Calcium is among the most versatile and precisely regulated second messengers, and in neurons its signalling logic is distinguished by extraordinary spatial and temporal resolution. Rather than acting as a uniform cytoplasmic signal, calcium operates through spatially confined microdomains that form within dendritic spines, postsynaptic compartments, and submembrane zones in response to synaptic activity and intracellular store release. The primary sources of postsynaptic calcium include NMDA receptors, voltage-gated calcium channels, and store-operated calcium entry mediated by the STIM-Orai axis at endoplasmic reticulum-plasma membrane junctions, with intracellular amplification through inositol trisphosphate receptors and ryanodine receptors establishing a rich repertoire of calcium dynamics that encode the pattern, frequency, and history of synaptic input. These signals are decoded by a suite of calcium-sensing proteins, most prominently calmodulin, which activates a network of downstream effectors including CaMKII, CaMKIV, calcineurin, and calpain. Through these transducers, calcium microdomains control the threshold for plasticity induction, regulating glutamate receptor trafficking, cytoskeletal remodelling, and the bidirectional modification of synaptic strength with remarkable spatial precision.

Beyond their local synaptic functions, calcium signals propagate into the dendritic shaft and nucleus, where they engage transcriptional programmes that consolidate synaptic changes into lasting structural and molecular remodelling. Nuclear calcium, derived both from cytoplasmic propagation and from calcium entry through nuclear envelope channels, activates CaMKIV and drives phosphorylation of CREB, initiating the expression of immediate early genes including Arc/Arg3.1, c-fos, and BDNF, as well as downstream late-response genes that reshape dendritic morphology, synaptic protein composition, and long-term circuit function. Calcium-dependent activation of transcription factors including Npas4, NFAT, MEF2, and SRF further diversifies the activity-dependent gene programme, with each pathway contributing distinct temporal and cell-type-specific outputs. The fidelity of these nucleus-directed signals depends on calcium buffering by endogenous proteins including calbindin and parvalbumin, on extrusion mechanisms at the plasma membrane and ER, and on the organisation of signalling microdomains that limit crosstalk between neighbouring cascades.

Disruption of calcium homeostasis and signalling fidelity is increasingly recognised as a core feature of neurological diseases: for example, presenilin mutations linked to familial Alzheimer’s disease alter ER calcium release and store-operated entry; dysregulated calcium handling contributes to excitotoxicity in stroke and epilepsy, and altered CaMKII and calcineurin signalling has been implicated in synaptic dysfunction across neurodevelopmental and neurodegenerative conditions, including Parkinson’s and polyglutamine disorders. Understanding how calcium signals are encoded, transduced, and translated into lasting changes in gene expression and synaptic structure therefore represents a fundamental challenge in molecular neuroscience with broad implications for the neurobiology of disease.

This Research Topic aims to bring together studies that dissect the molecular mechanisms by which calcium signals are generated, shaped, and interpreted across the postsynaptic compartment, dendritic arbour, and nucleus. This collection seeks to establish a unified framework for understanding how calcium microdomains and downstream signalling cascades link synaptic activity to lasting changes in gene expression, synaptic organisation, and neural circuit function by integrating biophysical, biochemical, cell-biological, and genomic perspectives,

We welcome submissions employing molecular, biochemical, electrophysiological, imaging, and genomic approaches, including studies using genetically encoded calcium indicators, optogenetic and chemogenetic tools for pathway manipulation, in vitro reconstitution, and proteomics or transcriptomics approaches connecting calcium signalling to gene regulatory outputs. Research using neuronal cultures, iPSC-derived systems, organoids, in vivo genetic models, and patient-derived material to link calcium signalling mechanisms to defined cellular, synaptic, or disease-relevant phenotypes is particularly encouraged. Contributions addressing calcium signalling across diverse neural cell types, brain regions, and developmental stages are welcome.

Topics of interest include, but are not limited to:

• Sources and spatial organisation of postsynaptic calcium signals, including NMDA receptor-dependent calcium entry, voltage-gated calcium channel subtypes, and the geometry of calcium nanodomains and microdomains in spines and dendrites
• Store-operated calcium entry in neurons and glia, including the molecular mechanisms of STIM and Orai proteins, endoplasmic reticulum-plasma membrane junctions, and their regulation by neuronal activity
• Intracellular calcium release through inositol trisphosphate receptors and ryanodine receptors, and the contribution of ER calcium stores to synaptic signalling and plasticity
• Calcium sensing by calmodulin and its activation of CaMKII, CaMKIV, calcineurin, and other effectors, including isoform-specific and localisation-dependent regulation
• Molecular mechanisms of long-term potentiation and depression, including calcium-dependent AMPA receptor trafficking, cytoskeletal dynamics, and spine structural remodelling
• Nuclear calcium signalling, including routes of calcium propagation to the nucleus, activation of CaMKIV and CREB, and the induction of immediate early and late-response gene programmes
• Calcium-dependent transcription factors including Npas4, NFAT, MEF2, and SRF, and their roles in shaping activity-dependent gene expression in neurons and glia
• Calcium buffering proteins and extrusion mechanisms, including calbindin, parvalbumin, PMCA, NCX, and SERCA, and their roles in shaping the amplitude, duration, and spatial spread of calcium signals
• Crosstalk between calcium signalling pathways and other second messenger systems, including cAMP-PKA, MAPK-ERK, and PI3K-Akt cascades, in the regulation of synaptic plasticity and gene expression
• Dysregulation of calcium homeostasis and signalling in neurological conditions, including Alzheimer’s disease, epilepsy, stroke, and neurodevelopmental disorders (see comment above)
• Novel tools for imaging, manipulating, and quantifying calcium signals and calcium-dependent signalling in neural cells, including genetically encoded calcium indicators, optogenetic actuators, and proximity labelling approaches