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

Abstract

Excitatory 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.

Drug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour

“…8g). This result was consistent with previous report that both Btg2 and Nr4a1 regulate neurogenesis and other brain functions via transcriptional mechanisms2223.…”

Cyclin-dependent Kinase 5 (Cdk5)-dependent Phosphorylation of p70 Ribosomal S6 Kinase 1 (S6K) Is Required for Dendritic Spine Morphogenesis

“…Alternatively the excitatory synapses might be shifted from the spines to dendritic shaft. This is consistent with a recent study showing a drastic reduction of spine density and abnormal distribution of excitatory synapses in neuron upon overexpression of the nuclear receptor Nr4a1 but no change in excitatory synaptic transmission (30). Besides simply acting as a site for excitatory synapse, dendritic spines offer additional properties for excitatory synaptic transmission, such as forming isolated compartments for Ca 2ϩ signaling and allowing modulation of synaptic strength as a result of rapid changes in spine size (31).…”

Cell-autonomous regulation of structural and functional plasticity in inhibitory neurons by excitatory synaptic inputs

“…3f), possibly reflecting a compensatory response to decreased excitatory inputs, consistent with observations of activitydependent redistribution of synapse in the absence of normal activity 21 .…”