TY - JOUR
T1 - Bidirectional perisomatic inhibitory plasticity of a Fos neuronal network
AU - Yap, Ee Lynn
AU - Pettit, Noah L.
AU - Davis, Christopher P.
AU - Nagy, M. Aurel
AU - Harmin, David A.
AU - Golden, Emily
AU - Dagliyan, Onur
AU - Lin, Cindy
AU - Rudolph, Stephanie
AU - Sharma, Nikhil
AU - Griffith, Eric C.
AU - Harvey, Christopher D.
AU - Greenberg, Michael E.
N1 - Funding Information:
Acknowledgements We thank all members of the Greenberg laboratory for discussions and critical feedback during the course of this work; all members of the Harvey laboratory for discussions and critical feedback; W. Regehr, D. Ginty, R. Wilson, C. Tzeng, J. Green, E. Pollina and T. Vierbuchen for feedback and critical evaluation of the data and/or manuscript; G. Fishell for the Dlx5/6Flpmice; L. Wu and the Harvard Genome Modification Facility for aiding in the generation of the Scg2fl/flmice; C. Wang and the Boston Children’s Hospital Viral Core for generation of AAVs; the Harvard Neurobiology Imaging Facility (NINDS P30 Core Center grant NS072030) for imaging support; and O. Mazor and P. Gorelik at the Harvard Research Instrumentation Core for technical design and support. This work was supported by NIH grants R01 NS028829 and R01 NS115965 (M.E.G.), NIH grant R01 NS089521 (C.D.H.), T32 NS007473 (C.P.D.), F32 NS112455 (C.P.D.), Stuart H.Q. and Victoria Quan fellowship (E-L.Y. and N.L.P.), Harvard Department of Neurobiology graduate fellowship (E.-L.Y.), and Aramont Fund for Emerging Science Research fellowship (E.-L.Y). In addition the Greenberg laboratory is supported by the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/2/4
Y1 - 2021/2/4
N2 - Behavioural experiences activate the FOS transcription factor in sparse populations of neurons that are critical for encoding and recalling specific events1–3. 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 not known whether 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-activated hippocampal CA1 pyramidal neurons by parvalbumin-expressing interneurons is enhanced, whereas perisomatic inhibition by cholecystokinin-expressing interneurons is weakened. This bidirectional modulation of inhibition is abolished when the function of the FOS transcription factor 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, a gene that encodes multiple distinct neuropeptides, to coordinate these changes in inhibition. As parvalbumin- and cholecystokinin-expressing interneurons mediate distinct features of pyramidal cell activity4–6, 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 theta phase are significantly altered in the absence 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 acting on distinct inhibitory pathways may support the consolidation of memories over time.
AB - Behavioural experiences activate the FOS transcription factor in sparse populations of neurons that are critical for encoding and recalling specific events1–3. 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 not known whether 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-activated hippocampal CA1 pyramidal neurons by parvalbumin-expressing interneurons is enhanced, whereas perisomatic inhibition by cholecystokinin-expressing interneurons is weakened. This bidirectional modulation of inhibition is abolished when the function of the FOS transcription factor 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, a gene that encodes multiple distinct neuropeptides, to coordinate these changes in inhibition. As parvalbumin- and cholecystokinin-expressing interneurons mediate distinct features of pyramidal cell activity4–6, 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 theta phase are significantly altered in the absence 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 acting on distinct inhibitory pathways may support the consolidation of memories over time.
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UR - http://www.scopus.com/inward/citedby.url?scp=85097321983&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-3031-0
DO - 10.1038/s41586-020-3031-0
M3 - Article
C2 - 33299180
AN - SCOPUS:85097321983
VL - 590
SP - 115
EP - 121
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7844
ER -