Mapping the transcriptional diversity of calcium signaling in the mouse and human brain.

Calcium (Ca2+) signaling is a key regulator of brain function and development. Here, we comprehensively analyze the Ca2+ signaling transcriptome in the adult mouse brain and the developing human brain to reveal the basis of signaling specificity. We show that neurons organize into non-stochastic Ca2+ states that reflect cell-type identity and capture subtle functional differences. These states arise from lineage-specific developmental Ca2+ programs that are detectable already in progenitor stages, and may precede differentiation into mature neuronal cell types. During neocortical development, many Ca2+ signaling genes, such as ADGRV1, NCALD, and CREB5, peak at distinct developmental stages, are evolutionarily conserved, and reflect transcriptional heterogeneity within progenitors associated with cell-fate decisions. Together, our findings provide an in-depth understanding of how a tightly regulated Ca2+ signaling transcriptome encodes cell-state-specific signaling programs and demonstrate that Ca2+ signaling is precisely tailored to distinct cell states.