Nr4a1 regulates cell-specific transcriptional programs in inhibitory GABAergic interneurons

Min Huang; Simon Pieraut; Jasmine Cao; Filip de Souza Polli; Vincenzo Roncace; Gloria Shen; Carlos Ramos-Medina; HeeYang Lee; Anton Maximov

doi:10.1016/j.neuron.2024.03.018

Nr4a1 regulates cell-specific transcriptional programs in inhibitory GABAergic interneurons

Neuron. 2024 May 13:S0896-6273(24)00196-X. doi: 10.1016/j.neuron.2024.03.018. Online ahead of print.

Authors

Min Huang¹, Simon Pieraut², Jasmine Cao², Filip de Souza Polli², Vincenzo Roncace², Gloria Shen², Carlos Ramos-Medina², HeeYang Lee¹, Anton Maximov³

Affiliations

¹ Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA; The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; The Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, CA 92037, USA.
² Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA; The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA; The Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: amaximov@scripps.edu.

PMID: 38754414
DOI: 10.1016/j.neuron.2024.03.018

Abstract

The patterns of synaptic connectivity and physiological properties of diverse neuron types are shaped by distinct gene sets. Our study demonstrates that, in the mouse forebrain, the transcriptional profiles of inhibitory GABAergic interneurons are regulated by Nr4a1, an orphan nuclear receptor whose expression is transiently induced by sensory experiences and is required for normal learning. Nr4a1 exerts contrasting effects on the local axonal wiring of parvalbumin- and somatostatin-positive interneurons, which innervate different subcellular domains of their postsynaptic partners. The loss of Nr4a1 activity in these interneurons results in bidirectional, cell-type-specific transcriptional switches across multiple gene families, including those involved in surface adhesion and repulsion. Our findings reveal that combinatorial synaptic organizing codes are surprisingly flexible and highlight a mechanism by which inducible transcription factors can influence neural circuit structure and function.

Keywords: GABAergic interneuron; Nr4a1; connectivity; hippocampus; immediate-early gene; inhibition; memory; sensory experience; synapse; transcription.