Synaptic activity suppresses expression of neurogenic differentiation factor 2 in an NMDA receptor-dependent manner

Neurogenic differentiation factor 2 (NeuroD2) is a highly expressed transcription factor in the developing central nervous system. In newborn neurons, NeuroD2-mediated gene expression promotes differentiation, maturation, and survival. In addition to these early, cell-intrinsic developmental processes, NeuroD2 in postmitotic neurons also regulates synapse growth and ion channel expression to control excitability. While NeuroD2 transactivation can be induced in an activity-dependent manner, little is known about how expression of NeuroD2 itself is regulated. Using genome-wide, mRNA-based microarray analysis, we found that NeuroD2 is actually one of hundreds of genes whose mRNA levels are suppressed by synaptic activity, in a manner dependent upon N-methyl d-aspartate receptor (NMDAR) activation. We confirmed this observation both in vitro and in vivo and provide evidence that this happens at the level of transcription and not mRNA stability. Our experiments further indicate that suppression of NeuroD2 message by NMDARs likely involves both CaMKII and MAPK but not voltage-gated calcium channels, in contrast to its mechanism of transactivation. We predict from these data that NMDARs may transduce information about the level of synaptic activity a developing neuron receives, to down-regulate NeuroD2 and allow proper maturation of cortical circuits by suppressing expression of neurite and synaptic growth promoting gene products.