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.