Bidirectional perisomatic inhibitory plasticity of a Fos neuronal network

Abstract

Behavioral experiences activate the Fos transcription factor (TF) in sparse populations of neurons that are critical for encoding and recalling specific events 1 – 3 . However, there is limited understanding of the mechanisms by which experience drives circuit reorganization to establish a network of Fos -activated cells. It is also 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 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 4 – 6 , 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 . These findings reveal an instructive role for Fos and Scg2 in establishing a network of Fos -activated neurons via the rewiring of local inhibition to form a selectively modulated state. The opposing plasticity mechanisms on distinct inhibitory pathways may support the consolidation of memories over time.

Roles and Transcriptional Responses of Inhibitory Neurons in Learning and Memory

“…However, multiple studies converge in indicating that memory encoding is also accompanied by an increase in inhibitory drive directly onto activated pyramidal neurons. For instance, recent evidence finely identifies mechanisms regulating the perisomatic inhibitory plasticity onto activated CA1 pyramidal neurons ( Yap et al, 2021 ). The authors observed that an enhanced and persistent perisomatic inhibition by PV+ interneurons onto Fos-activated pyramidal cells was counterbalanced by a weaker perisomatic inhibition by cholecystokinin expressing basket cells (CCKBC) ( Yap et al, 2021 ).…”

“…For instance, recent evidence finely identifies mechanisms regulating the perisomatic inhibitory plasticity onto activated CA1 pyramidal neurons ( Yap et al, 2021 ). The authors observed that an enhanced and persistent perisomatic inhibition by PV+ interneurons onto Fos-activated pyramidal cells was counterbalanced by a weaker perisomatic inhibition by cholecystokinin expressing basket cells (CCKBC) ( Yap et al, 2021 ). This bidirectional inhibition was regulated by Fos-induced Scg2 expression, whose suppression was shown to disrupt hippocampal network oscillations.…”

“…Overall, activity-dependent transcriptional responses of both excitatory and inhibitory cortical neurons appear to converge in increasing the inhibitory tone onto activated excitatory neurons. Similarly, in the hippocampus, Fos expression in activated excitatory neurons induces the LRG Scg2, a precursor to four neuropeptides, which increases perisomatic inhibition by PV-interneurons albeit weakening that of CCK-interneurons ( Yap et al, 2021 ).…”

“…Finally, a recently published study investigated how activity-dependent transcription, triggered by exploration of a novel environment, drives circuit reorganization by modulating perisomatic inhibitory plasticity onto CA1 pyramidal hippocampal neurons ( Yap et al, 2021 ). The authors focus on the Fos-dependent transcriptional cascade in these cells to characterize LRGs that are responsible for the observed increase in inhibition by PV-interneurons and weakening of CCK-interneurons inputs.…”

Simultaneous single cell measurements of intranuclear proteins and gene expression

“…signals [31][32][33][34] , where they activate the expression of diverse pathways related to inflammation, oncogenesis, apoptosis, cell proliferation, and synaptic remodeling [35][36][37][38][39][40][41][42][43] .…”