Sven Loebrich and Elly Nedivi Physiol Rev 89:1079-1103, 2009. doi:10.1152/physrev.00013.2009 You might find this additional information useful... This article cites 293 articles, 112 of which you can access free at: http://physrev.physiology.org/cgi/content/full/89/4/1079#BIBL Medline items on this article's topics can be found at http://highwire.stanford.edu/lists/artbytopic.dtl on the following topics: Physiology .. Synaptic Transmission Physiology .. Neuronal Activity Oncology .. Transcriptional Regulation Medicine .. Genes Updated information and services including high-resolution figures, can be found at: http://physrev.physiology.org/cgi/content/full/89/4/1079 Additional material and information about Physiological Reviews can be found at: http://www.the-aps.org/publications/prv Downloaded from This information is current as of September 30, 2009 . physrev.physiology.org on September 30, 2009 Physiological Reviews provides state of the art coverage of timely issues in the physiological and biomedical sciences. It is published quarterly in January, April, July, and October by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2005 by the American Physiological Society. ISSN: 0031-9333, ESSN: 1522-1210. Visit our website at http://www.the-aps.org/. Physiol Rev 89: 1079–1103, 2009; doi:10.1152/physrev.00013.2009. The Function of Activity-Regulated Genes in the Nervous System SVEN LOEBRICH AND ELLY NEDIVI The Picower Institute for Learning and Memory, Departments of Brain and Cognitive Sciences and of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts I. Introduction 1079 II. Transcriptional Activation of Immediate Early Genes in the Nervous System 1080 III. Transcriptional Activation as the Basis for Long-Term Synaptic Plasticity 1081 Downloaded from IV. Search for Activity-Regulated Genes 1083 V. Implementation of Activity-Dependent Neuronal Transcriptional Programs 1086 A. Intracellular signaling molecules 1086 B. Extracellular signaling molecules 1087 C. Regulation of the synaptic machinery 1090 D. Activity-regulated genes coordinating inhibitory synapse formation 1093 VI. Summary 1094 physrev.physiology.org Loebrich S, Nedivi E. The Function of Activity-Regulated Genes in the Nervous System. Physiol Rev 89: 1079–1103, 2009; doi:10.1152/physrev.00013.2009.—The mammalian brain is plastic in the sense that it shows a remarkable capacity for change throughout life. The contribution of neuronal activity to brain plasticity was first recognized in relation to critical periods of development, when manipulating the sensory environment was found to profoundly affect neuronal morphology and receptive field properties. Since then, a growing body of evidence has established that brain plasticity extends beyond development and is an inherent feature of adult brain function, spanning on September 30, 2009 multiple domains, from learning and memory to adaptability of primary sensory maps. Here we discuss evolution of the current view that plasticity of the adult brain derives from dynamic tuning of transcriptional control mechanisms at the neuronal level, in response to external and internal stimuli. We then review the identification of “plasticity genes” regulated by changes in the levels of electrical activity, and how elucidating their cellular functions has revealed the intimate role transcriptional regulation plays in fundamental aspects of synaptic transmission and circuit plasticity that occur in the brain on an every day basis. I. INTRODUCTION transcriptional activity. The study of tumor viruses and their mechanism of action opened the door to our under- Groundbreaking work in the 1960s and 1970s dem- standing of the cellular pathways that control cell growth onstrated that brain plasticity is shaped by sensory input and proliferation, and in the mature nervous system me- during critical periods of development. Experimental ma- diate neuronal responses to electrical activity. nipulation of the sensory environment was shown to pro- The first molecules shown to translate extracellular foundly affect neuronal morphology and receptive field signals to transcriptional programs that alter cell proper- properties (120, 160, 274). Later studies demonstrated ties were transcription factors activated within minutes of that brain plasticity is not limited to development but stimulation by growth factors and encoded by the cellular persists in adulthood and seems to be an inherent feature counterparts of tumor virus oncogenes. Early studies of of everyday brain function, critical for learning and mem- the Rous sarcoma virus (RSV) revealed that its transform- ory, and the adaptability of primary sensory maps (re- ing function resided in a single gene called src (25, 125, viewed in Refs. 31, 114, 116, 180, 278). 210). In work for which they received the Nobel prize, The understanding of neuronal adaptability in re- Bishop and Varmus (210) showed that the viral src gene, sponse to the external environment is largely owed to the v-src, was derived from a normal cellular protooncogene discovery in other cell systems of signal transduction c-src. Clues to the machinery of intercellular signaling via pathways that couple extracellular cues to changes in growth factors and mitogens came when it was discov- www.prv.org 0031-9333/09 $18.00 Copyright © 2009 the American Physiological Society 1079 1080 SVEN LOEBRICH AND ELLY NEDIVI ered that in normal cells protooncogenes function in sig- plexity to the regulation of cAMP-induced transcription naling roles that regulate cell growth and proliferation (154). (189, 256, 272). Cellular oncogenes were found to encode In 1989, Gonzalez and Montminy (94) demonstrated proteins that represent all major components of the that phosphorylation is a key mechanism in CREB regu- growth factor response pathway: from the growth factor lation. They showed that elevated cAMP levels led to sis (42, 62, 133, 134) and growth factor receptor erbB (64, phosphorylation of CREB at a specific residue, serine-133. 218), to the small G protein ras (59, 189, 256) or nonre- Phosphorylation of CREB at this particular residue is a ceptor tyrosine kinase src (25, 125, 210), and finally nu- prerequisite for its ability to trigger gene transcription in clear proteins, such as myc (3, 71, 105, 146), fos (55), or trans, as was first assessed for the somatostatin gene jun (26, 88, 202). (94). The phosphorylated CREB protein associates with It was known that application of growth factors like CBP (CREB-binding protein) (45) and mediates interac- platelet-derived growth factor (PDGF) leads to rapid ac- tion with TFIIB, a major component of the transcription tivation of gene expression despite the presence of pro- machinery of the RNA polymerase II complex (150). Ter- tein synthesis inhibitors such as cycloheximide. These mination of CREB signaling can be achieved by dephos- rapid response genes were termed immediate-early genes phorylation through protein phosphatase 1 (PP-1), or (IEGs) (46). Nuclear run-off transcription assays after PP-2a (201). Downloaded from growth factor treatment revealed that the protoonco- In parallel to in-depth studies of protooncogene genes c-fos and c-myc were among the IEGs (96, 190). IEGs, such as c-fos, other studies greatly expanded the Several facts implicated c-fos in regulation of gene expres- pool of known inducible genes by administering different sion. It was known to encode a nuclear protein (55) stimuli, such as mitogens and phorbol esters (4, 155, 161, associated with chromatin and capable of binding DNA 253), leading to the more general view that gene transcrip- cellulose in vitro (226, 233). It turned out that c-fos and tion in the nucleus is part of the cellular response pro- physrev.physiology.org c-jun are specific members of inducible gene families gram to alterations in signaling from outside the cell. An whose products associate combinatorially to form integral aspect of this cellular response program is the dimeric complexes that function as transcriptional ac- biphasic nature of transcriptional activation, with IEG tivators (54). These transcription factors, in turn, help induction closely followed by expression of a second induce expression of second wave genes, termed de- wave of delayed early genes. Another important feature is layed early genes. that multiple signals and intracellular pathways can influ- Studies of the protooncogene c-fos also pioneered ence IEG transcriptional activation via an assortment of the identification of cis- and trans-acting regulatory ele- cis- and trans-acting elements, and nuclear IEGs them- on September 30, 2009 ments that play a role in controlling IEG induction (269). selves comprise a diverse array of factors that can poten- The first operationally defined regulatory cis-element, the tially act combinatorially to differentially affect distinct serum response element (SRE), was initially mapped in second wave gene sets. the promoter region of the c-fos gene (91, 219, 260). The c-fos promoter was also found to contain a cAMP respon- sive element (CRE) (243), common to cAMP-regulated II. TRANSCRIPTIONAL ACTIVATION OF genes (185). The search for trans-acting protein factors IMMEDIATE EARLY GENES IN THE that bind to CRE identified a bZip transcription factor NERVOUS SYSTEM termed CREB (CRE-binding protein) (111). The CREB protein family was found to comprise more than 10 mem- Generalization of these concepts to neurons started bers (102) able to heterodimerize in multiple combina- before they were