Synapse-to-Nucleus Communication through NFAT Is Mediated by L-type Ca 2+ Channel Ca 2+ Spike Propagation to the Soma

Cell Rep. 2019 Mar 26;26(13):3537-3550.e4. doi: 10.1016/j.celrep.2019.03.005.

Abstract

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.

Keywords: AKAP79/150; Ca(v)1; L-type calcium channel; NFAT; calcineurin; calcium spike; excitation-transcription coupling; glutamate uncaging; microfluidic; synapse to nucleus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Calcium Channels, L-Type / metabolism*
  • Cell Communication
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Female
  • Hippocampus / cytology
  • Humans
  • Male
  • Models, Neurological
  • NFATC Transcription Factors / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / metabolism*
  • Synaptic Potentials

Substances

  • Calcium Channels, L-Type
  • NFATC Transcription Factors