Single-Cell Transcriptomics Reveals the Molecular Logic Underlying Ca ²⁺ Signaling Diversity in Human and Mouse Brain

The calcium ion (Ca ²⁺ ) is a ubiquitous intracellular signaling molecule that plays a critical role in the adult and developing brain. However, the principles governing the specificity of Ca ²⁺ signaling remain unresolved. In this work, we comprehensively analyzed the Ca ²⁺ signaling transcriptome in the adult mouse brain and developing human brain. We found that neurons form non-stochastic Ca ²⁺ -states that are reflective of their cell types and functionality, with evidence suggesting that the diversity is driven by lineage-specific developmental changes. Focusing on the neocortical development, we reveal that an unprecedented number of Ca ²⁺ genes are tightly regulated and evolutionarily conserved, capturing functionally driven differences within radial glia and neuronal progenitors. In summary, our study provides an in-depth understanding of the cellular and temporal diversity of Ca ²⁺ signaling and suggests that Ca ²⁺ signaling is dynamically tailored to specific cell states.