Bidirectional perisomatic inhibitory plasticity of a Fos neuronal network [Ribotag]

Behavioral experiences activate the Fos transcription factor (TF) in sparse populations of neurons that are critical for encoding and recalling specific events. However, there is limited understanding of the mechanisms by which experience drives circuit reorganization to establish a network of Fos-activated cells. Additionally, it is unknown if Fos is required in this process beyond serving as a marker of recent neural activity and, if so, which of its many gene targets underlie circuit reorganization. Here we demonstrate that when mice engage in spatial exploration of novel environments, perisomatic inhibition of Fos-expressing hippocampal CA1 pyramidal neurons by parvalbumin (PV)-interneurons (INs) is enhanced, while perisomatic inhibition by cholecystokinin (CCK)-INs is weakened. This bidirectional modulation of inhibition is specific to Fos-expressing neurons and is abolished when the function of the Fos TF complex is disrupted. Single-cell RNA-sequencing, ribosome-associated mRNA profiling, and chromatin analyses, combined with electrophysiology reveal that Fos activates the transcription of Scg2 (secretogranin II), a gene that encodes multiple distinct neuropeptides, to coordinate these changes in inhibition. As PV- and CCK-INs mediate distinct features of pyramidal cell activity, the Scg2-dependent reorganization of inhibitory synaptic input might be predicted to affect network function in vivo. Consistent with this prediction, hippocampal gamma rhythms and pyramidal cell coupling to CA1 theta are significantly altered with loss of Scg2. Together these findings reveal an instructive role for Fos and Scg2 in establishing a network of Fos-activated neurons via the rewiring of local inhibition from an initially broad to a selectively modulated state. The opposing plasticity mechanisms on distinct inhibitory pathways may support the consolidation of memories over time. Overall design: CaMK2a-Cre; lox-STOP-lox-Rpl22-HA or PV-Cre; lox-STOP-lox-Rpl22-HA mice were intraperitoneally injected with kainic acid (KA) or phosphate buffered saline (PBS). After 6 hours, hippocampal CA1 tissue was rapidly dissected from mice and subsequently used for isolation of ribosome-bound mRNAs. Immunopurification of ribosome-bound mRNAs was performed as previously described (Sanz PNAS 2009) with 10mM Ribonucleoside Vanadyl Complex present in the lysis buffer and using the mouse monoclonal anti-HA antibody (Sigma HA-7, H3663, 12 ug/IP). A small fraction of lysate before the immunoprecipitation (IP) was used as input for each sample. For CaMK2a-Ribotag, 3 bioreplicates were used per condition, with CA1 tissue from 4 mice pooled per bioreplicate. For PV-Ribotag, 4 bioreplicates were used per condition, with CA1 tissue from 9-10 mice pooled per bioreplicate.