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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. [ABSTRACT FROM AUTHOR]

Cover illustration: The cover image, by Fading Chen and Benjamin J. Hall, is based on the Research Article Synaptic activity suppresses expression of neurogenic differentiation factor 2 in an NMDA receptor‐dependent manner, DOI: 10.1002/syn.21986. [ABSTRACT FROM AUTHOR]

The postnatal maturation of glutamatergic synapses involves a change in composition and functional contribution of postsynaptic receptors. Developing cortical synapses are dominated by NMDA receptors (NMDARs) containing NR2B subunits and are characterized by a low ratio of AMPA/NMDA receptor-mediated current. Synapse maturation is marked by the incorporation of NR2A-containing NMDA receptors and an increase in the AMPA/NMDA current ratio. We show here that NMDARs containing the NR2B subunit regulate glutamatergic transmission at developing synapses by negatively influencing the synaptic incorporation of AMPA receptors (AMPARs). Genetic removal of NR2 Bleads to increased surface expression and synaptic localization of AMPA receptor subunits and a corresponding increase in AMPAR-mediated synaptic current. Enrichment of synaptic AMPARs, in the absence of NR2B signaling, is associated with increased levels of transmembrane AMPAR regulatory protein (TARP) expression and is blocked by expression of a dominant-negative TARP construct (γ-2ΔC). These observations suggest that NR2B signaling limits AMPA receptor incorporation at developing synapses by negatively regulating TARP expression and provide a mechanism to explain the maintenance of low AMPA/NMDA ratio at immature glutamatergic synapses. [ABSTRACT FROM AUTHOR]

A single, low dose of ketamine evokes antidepressant actions in depressed patients and in patients with treatment-resistant depression (TRD). Unlike classic antidepressants, which regulate monoamine neurotransmitter systems, ketamine is an antagonist of the N-methyl- d -aspartate (NMDA) family of glutamate receptors. The effectiveness of NMDAR antagonists in TRD unveils a new set of targets for therapeutic intervention in major depressive disorder (MDD) and TRD. However, a better understanding of the cellular mechanisms underlying these effects is required for guiding future therapeutic strategies, in order to minimize side effects and prolong duration of efficacy. Here we review the evidence for and against two hypotheses that have been proposed to explain how NMDAR antagonism initiates protein synthesis and increases excitatory synaptic drive in corticolimbic brain regions, either through selective antagonism of inhibitory interneurons and cortical disinhibition, or by direct inhibition of cortical pyramidal neurons. This article is part of the Special Issue entitled ‘Synaptopathy – from Biology to Therapy’. [ABSTRACT FROM AUTHOR]