Neuronal FOS reports synchronized activity of presynaptic neurons

Abstract

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. Here we use optogenetic stimulation of hippocampal neurons to investigate the relation between spike frequency and FOS expression, and report several 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 and, at 0.1 Hz, FOS is induced independently of CREB/calcineurin/MEK pathways. We propose that FOS does not primarily encode a neuron's own spike frequency but indicates repeated participation in highly synchronized activity, e.g. sharp wave ripples.

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“…In the granule cells, for example, kindled seizures causing action potentials led to cFos expression, but the same stimulation in the substantia nigra failed to do so (38). In the hippocampal CA2, on the other hand, spiking at 0.1 Hz, but not at 50 Hz, was successful in evoking cFos expression, which indicated participation of the neuron in synchronised synaptic activity (39). Interestingly, cFos expression in magnocellular SON OXT neurons is only seen after synaptic activity induced by an OXT-receptor agonist (40).…”

Only Hit the Bad Guys: A Gene Therapy Approach to Selectively Silence Highly Active Neurons Reduces Chronic Seizures in Epileptic Mice

“…Finally, while expression of the c-Fos protein (driven by the cfos promotor) has traditionally been used to indicate when a cell has recently been active, the relationship between cellular activity and c-Fos expression is not entirely clear and is still actively being investigated. 8 Thus, continued refinement of the selective activity-dependent promoters and inhibitory payloads that will best control the symptoms of epilepsy will be critical to improving the clinical outcomes of this exciting technological development.…”