Current Drug Targets - CNS & Neurological Disorders, 2005, 4, 481-497 481 1568-007X/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd. CREB, Synapses and Memory Disorders: Past Progress and Future Challenges Sheena A. Josselyn *,1,2 and Peter V. Nguyen 3 1 Program in Integrative Biology and Brain & Behaviour, Hospital for Sick Children Research Institute, 555 University Ave., Toronto, ON, Canada M5G 1X8 2 Department of Physiology, University of Toronto, Toronto, ON, Canada 3 Departments of Physiology and Psychiatry, and Centre for Neuroscience, University of Alberta School of Medicine, Edmonton, Alberta, T6G 2H7, Canada Abstract: In neurons, appropriate long-term adaptive responses to changes in the environment require the conversion of extracellular stimuli into discrete intracellular signals. Many of these signals involve the regulation of gene expression. The cAMP responsive element binding protein (CREB) is a nuclear transcription factor that modulates transcription of genes containing cAMP responsive elements (CRE sites) in their promoters. CREB is a key part of many intracellular signaling events that critically regulate many neural functions. Numerous studies on invertebrates and vertebrates demonstrate that CREB is critical for long-term memory. Here, we review the key features of CREB-dependent transcription and critically evaluate the data examining the roles of CREB in different forms of plasticity, including long- term memory in mammals. Because learning and memory have been linked to specific types of synaptic plasticity in several species, we also review studies on the role of CREB in long-term facilitation in Aplysia and in hippocampal long- term potentiation (LTP). Several human cognitive disorders have been linked to alterations of CREB-regulated gene expression. Therefore, we explore the possibility of targeting CREB function in developing novel treatment strategies. Finally, we highlight areas of research on CREB that are ripe for further advancement. INTRODUCTION Memories may persist for dramatically different lengths of time, from seconds and minutes to a lifetime. Different forms of memory have distinct molecular requirements. Short-term memory (STM) persists for minutes to hours and is thought to be mediated by covalent modifications of existing synaptic molecules, such as phosphorylation or dephosphorylation of enzymes, receptors or ion channels [1]. In contrast, long-term memory (LTM) persists for days or longer, and is thought to be mediated by growth of new synapses and restructuring of existing synapses [2]. There is extensive evidence from several species that, unlike STM, LTM requires the transcription and translation of new proteins [3, 4]. This raises the key question: Which transcription factors are critical for expression of LTM? One attractive candidate for coupling neuronal activation that occurs during learning with the gene expression required for LTM is cyclic-AMP (cAMP; cyclic adenosine 3’,5’- monophosphate) responsive element binding protein (CREB). CREB is a family of transcription factors that modulates the transcription of genes that contain cAMP responsive elements (CRE) in their promoter regions. Although a wealth of convergent evidence from studies using invertebrate and vertebrate species shows that the CREB family of genes is important for LTM, recent studies have questioned whether CREB is truly critical for LTM *Address correspondence to the author at the Program in Integrative Biology and Brain & Behaviour, Hospital for Sick Children Research Institute, 555 University Ave., Toronto, ON, Canada M5G 1X8; E-mail: Sheena.josselyn@sickkids.ca formation in mammals [5]. This review provides a detailed examination of the evidence for and against the involvement of CREB in LTM and synaptic plasticity. We then review the neurobiology of CREB and related pathways and discuss the possibility of targeting CREB for the treatment of memory disorders. CREB: PROPERTIES, BIOCHEMISTRY, STRUCTURE, AND SIGNALING PATHWAYS LEADING TO ACTIVATION OF CREB CREB is a member of a family of structurally related transcription factors. In mammals, at least three genes encode CREB-like proteins: CREB, CREM (cAMP Response Element Modulator) and ATF-1 (Activating Transcription Factor 1) [6-8]. The mouse and human CREB gene is comprised of 11 exons [9-11], and alternative splicing generates the three major activator isoforms of CREB: , , and  [12-14]. In addition to these transcriptional activators, the CREB family also includes transcriptional repressors. For example, the CREM gene codes several isoforms that repress CRE-dependent transcription: the CREM ,  and  isoforms, as well as the inducible cyclic-AMP early repressor (ICER) [15, 16]. CREB, CREM and ATF1 proteins share a conserved basic leucine zipper (bZip) domain that is responsible for dimerization between CREB family members and DNA binding [17]. Two glutamine-rich constitutive activation domains (Q1 and Q2) flank a kinase-inducible transactivation domain (KID) that contains a key phosphorylation site, initially characterized as being regulated by cAMP-dependent protein kinase (PKA). Although CREB may be phosphorylated at a number of