Synapse-to-Nucleus Communication through NFAT Is Mediated by L-type Ca²⁺ Channel Ca²⁺ Spike Propagation to the Soma

Long-term information storage in the brain requires continual modification of the neuronal transcriptome. Synaptic inputs located hundreds of micrometers from the nucleus can regulate gene transcription, requiring high-fidelity, long-range signaling from synapses in dendrites to the nucleus in the cell soma. Here, we describe a synapse-to-nucleus signaling mechanism for the activity-dependent transcription factor NFAT. NMDA receptors activated on distal dendrites were found to initiate L-type Ca²⁺ channel (LTCC) spikes that quickly propagated the length of the dendrite to the soma. Surprisingly, LTCC propagation did not require voltage-gated Na⁺ channels or back-propagating action potentials. NFAT nuclear recruitment and transcriptional activation only occurred when LTCC spikes invaded the somatic compartment, and the degree of NFAT activation correlated with the number of somatic LTCC Ca²⁺ spikes. Together, these data support a model for synapse to nucleus communication where NFAT integrates somatic LTCC Ca²⁺ spikes to alter transcription during periods of heightened neuronal activity.