Kim et al. Experimental & Molecular Medicine (2018) 50:11 DOI 10.1038/s12276-018-0025-1 Experimental & Molecular Medicine REVIEW ARTICLE Open Access Synapse development organized by neuronal activity-regulated immediate- early genes Seungjoon Kim1, Hyeonho Kim1 and Ji Won Um1 Abstract Classical studies have shown that neuronal immediate-early genes (IEGs) play important roles in synaptic processes critical for key brain functions. IEGs are transiently activated and rapidly upregulated in discrete neurons in response to a wide variety of cellular stimuli, and they are uniquely involved in various aspects of synapse development. In this review, we summarize recent studies of a subset of neuronal IEGs in regulating synapse formation, transmission, and plasticity. We also discuss how the dysregulation of neuronal IEGs is associated with the onset of various brain disorders and pinpoint key outstanding questions that should be addressed in this field. Introduction experience-dependent synaptic changes and maturation Numerous studies have shown that neural activity plays of neural circuits. an important role in regulating synaptic strength, neuro- More than dozens of neuronal IEGs were identified by fi 1– 12 1234567890():,; 1234567890():,; nal membrane properties, and neural circuit re nement Paul Worley, Elly Nedivi, and colleagues , owing to the 3. In particular, sensory experiences continually influence use of the subtractive hybridization method, in combi- brain development at synaptic, circuit, and organismal nation with various neural stimulation protocols, most levels, as Hubel4 and Wiesel5 elegantly demonstrated in notably seizure paradigms. Among them, cAMP- their work on visual cortex organization during the cri- responsive element-binding protein (CREB) has been tical period5. The effects of sensory experience are man- the most studied in regulating activity-dependent synapse ifested by neurotransmitter release at presynaptic development and plasticity13. Its physiological significance terminals, their reception at postsynaptic membranes, and in neuronal development and cognitive behaviors has depolarization of postsynaptic neurons by increased been consistently shown across a variety of model concentration of cytoplasmic calcium. This increase in organisms including mouse, Drosophila, and Aplysia13.In cytoplasmic calcium activates a program of gene expres- addition to CREB, other IEGs have been extensively – sion in the nucleus6 9. Including classic immediately-early investigated12. Intriguingly, distinct IEGs are influenced genes (IEGs) such as Fos and Jun, a number of activity- by neuronal stimulation or activity blockade in a pathway- regulated transcription factors have been identified and specific and stimulus-specific manner. For example, Egr1 3,10,11 extensively investigated . These studies have led to an mRNA levels are N-methyl-D-aspartate-type glutamate important hypothesis that transcriptional regulation is a receptor-dependent, whereas c-fos levels are not14,15. key mechanism by which neuronal activity can trigger Moreover, different IEGs exhibit distinct temporal win- dow with different activation kinetics. Synaptic activity also drives long-term changes in neuronal structure and Correspondence: Ji Won Um ([email protected]) function, contributing to learning and memory, via 1 Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of mechanisms involving transcriptional activation through Science and Technology (DGIST), Daegu 42988, Korea These authors contributed equally: Seungjoon Kim, Hyeonho Kim. © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Kim et al. Experimental & Molecular Medicine (2018) 50:11 Page 2 of 7 Fig. 1 Distinct actions of Arc, Npas4, and Homer1a at excitatory and inhibitory synapses. Neuronal activation induces rapid transcription of immediate-early genes (IEGs) such as Npas4, Arc, and Homer1a. Npas4 regulates the transcription of its downstream target genes including BDNF to regulate inhibitory synapse development. Arc is targeted to activated excitatory synapses and facilitates AMPA receptor endocytosis through interaction with dynamin and endophilin, resulting in long-term depression. Homer1a is also specifically targeted to excitatory synapses, where it competes with other Homer proteins to interact with Homer-binding proteins such as mGluRs, Shanks, and IP3R and negatively acts in regulating excitatory synapse structure, function, and plasticity second messenger systems16. A mechanistic concept for Induction of Arc levels in an activity-dependent manner differential regulation of neuronal IEGs was utilized for significantly elevates the proportion of thin spines and mapping specific neural functions onto neuronal activity reduces surface α-amino-3-hydroxy-5-methyl-4-iso- in different brain regions17. xazolepropionic acid (AMPA) receptor density, which In the current review, we discuss three exemplary IEGs prevents network hyperexcitability, and contributes to (activity-regulated cytoskeleton-associated protein (Arc/ maintenance of neuronal circuit homeostasis26. Arc Arg3.1), neuronal Per/Arnt/Sim (PAS) domain protein 4 induction is also required for late long-term potentiation – (Npas4), and Homer protein homolog 1a (Homer1a)) that (LTP) and memory consolidation27 29, which is regulated play important roles in distinct facets of synapse and by local actin polymerization28. Arc knockout (KO) mice neural circuit development, as excellent reviews for the exhibited a failure to form long-term memories, while other neuronal IEGs are available. We describe the their short-term memories were intact29. These beha- involvement of the three IEGs in synapse formation, vioral defects are associated with the alteration in LTP transmission, plasticity, and cognitive behaviors. We also in vivo. In addition, Arc mediates metabotropic glutamate discuss the possible implications of these proteins in some receptor (mGluR)-dependent long-term depression – brain disorders. through facilitation of AMPA receptor endocytosis30 33 (Fig. 1). One of the proposed mechanisms by which Arc Activity-regulated cytoskeleton-associated protein plays a regulatory role in AMPA receptor trafficking is via Arc (also known as Arg3.1) is one of the most tightly its interaction with components of the endocytic – regulated molecules18 20. Neuronal activity regulates its machinery, dynamin-2 and endophilin-330. Calcium/cal- transcription, translation, trafficking, localization, and modulin-dependent protein kinase IIβ plays a role in the stability21,22. Unlike other IEG products, Arc is not a targeting of synaptic activity-induced Arc to strong sti- transcription factor, but acts as an effector involved in mulation experienced-inactive synapses where Arc med- various neuronal signaling pathways. Thus, Arc mRNA is iates AMPA receptor clearance34. Arc is also required for – rapidly transcribed in response to neuronal activity, and homeostatic plasticity35 37. In particular, visual precisely targeted to activated synapses in neuronal den- experience-induced Arc controls internalization of AMPA – drites23 25. receptors, and as such, regulates homeostatic plasticity of excitatory synaptic transmission in layer 2/3 neurons of Official journal of the Korean Society for Biochemistry and Molecular Biology Kim et al. Experimental & Molecular Medicine (2018) 50:11 Page 3 of 7 the visual cortex36. Arc KO mice displayed abnormal in the number of inhibitory synapses on the soma, and ocular dominance plasticity38, suggesting that Arc is concurrently, a decrease in the number of inhibitory required for the experience-dependent processes that synapses on the apical dendrites of CA1 hippocampal establish synaptic connections in visual cortex. pyramidal neurons53. Mechanistically, the inhibition In addition to regulating synaptic plasticity, Arc is mode within these subcellular compartments appears to involved in synaptic pruning. Specifically, Arc mediates be differentially tuned by distinct sets of Npas4 down- elimination of redundant climbing axons to Purkinje cell stream targets. For instance, brain-derived neurotrophic in the developing cerebellum39. Neuronal activity- factor (BDNF) specifically mediates Npas4-mediated dependent myocyte enhancer factor 2 (MEF2) generates somatic inhibition (Fig. 1), while other downstream tar- Arc transcripts, and subsequently activates local dendritic gets (mostly uncharacterized) are thought to mediate mGluR5 proteins to promote the translation of MEF2- dendritic inhibition. In addition, Npas4