Activity-Induced Nr4a1 Regulates Spine Density and Distribution Pattern of Excitatory Synapses in Pyramidal Neurons

•Nr4a1 expression is bidirectionally regulated by NMDA receptor activity•Nr4a1 overexpression eliminates spines without weakening excitatory synapse•Loss of Nr4a1 increases spine density specifically at the distal ends of dendrites•Nr4a1 coordinately regulates Plk2 and Rac1/RhoA pathways leading toward spine loss

SummaryExcitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses.