The immediate early gene FOS is frequently used as a marker for highly active neurons. Implicit in this use is the assumption that there is a correlation between neuronal spiking and FOS expression. Using optogenetic stimulation of hippocampal neurons to investigate the relation between spike frequency and FOS expression, we made some surprising observations. First, FOS expression is cell-type specific, spiking CA2 pyramidal neurons rarely express FOS. Second, FOS has a U-shaped dependence on frequency: Spiking at 0.1 Hz is more effective than high frequency spiking (50 Hz) while intermediate frequencies do not induce FOS. Third, the pathway from spiking to FOS is not cell-autonomous. Instead, transmitter release and metabotropic glutamate receptor (mGluR) activation are required, inducing FOS independent of CREB/calcineurin/MEK pathways. We propose that FOS does not primarily encode a neuron’s own spike frequency, but repeated participation in highly synchronized activity, e.g. sharp wave ripples.