Essential function of Nr4a2 in subicular development and social novelty.

INTRODUCTION

The subicular regions are a major output hub of the hippocampus. Recent studies have shown that subicular neurons are highly diverse in their gene expression patterns, neural circuitry, and electrophysiological properties. However, the developmental transcriptional program underlying their specification remains poorly understood.

OBJECTIVES

To delineate how the orphan nuclear receptor Nr4a2 orchestrates both the developmental specification and functional maintenance of subicular neurons, and to uncover the underlying molecular mechanisms.

METHODS

Nr4a2 conditional knockout (CKO) mice and adult subicular-specific AAV-Nr4a2 CKO mice were comprehensively profiled using RNA-seq, CUT&Tag, immunohistochemistry, slice electrophysiology, and behavioural assays to elucidate the developmental and functional sequelae of Nr4a2 ablation.

RESULTS

In this study, using conditional genetic models targeting the orphan nuclear receptor Nr4a2, we demonstrate that Nr4a2 is essential for both the acquisition and maintenance of the molecular identity of subiculum proper (Sub) neurons, as well as for establishing its connectivity with the retrosplenial cortex (Rsp) during embryonic development and adulthood. Loss of Nr4a2 in subicular regions results in deficits in social novelty in mice. Furthermore, we show that Nr4a2 can directly bind to the promoters of Sub-enriched genes and promote their transcription in vivo.

CONCLUSION

Together, these findings reveal a pivotal role for Nr4a2 in establishing the genetic identity and connectivity of Sub neurons and suggest that its dysfunction may contribute to hippocampus-related neurodevelopmental disorders.